Template-fixed peptidomimetics with antimicrobial activity

ABSTRACT

Template-fixed β-hairpin peptidomimetics of the general formulae (I) and (II) wherein Z, Z1 and Z2 are template-fixed chains of 8 to 16 α-amino acid residues which, depending on their positions in the chain (counted starting from the N-terminal amino acid) are Gly, or Pro, or of certain types which, as the remaining symbols in the above formulae, are defined in the description and the claims, and salts thereof, have the property to inhibit the growth of or to kill microorganisms and cancer cells. They can be used as disinfectants for foodstuffs, cosmetics, medicaments or other nutrient-containing materials or as medicaments to treat or prevent infections or diseases related to such infections and/or cancer. These β-hairpin peptidomimetics can be manufactured by a process which is based on a mixed solid- and solution phase synthetic strategy.

[0001] The present invention provides template-fixed β-hairpinpeptidomimetics incorporating template-fixed chains of 8 to 16 α-aminoacid residues which, depending on their positions in the chains, are Glyor Pro, or of certain types, as defined hereinbelow. Thesetemplate-fixed β-hairpin mimetics have broad spectrum antimicrobial andanticancer activity. In addition, the present invention provides anefficient synthetic process by which these compounds can, if desired, bemade in parallel library-format. These β-hairpin peptidomimetics showimproved efficacy, bioavailability, half-life and most importantly asignificantly enhanced ratio between antibacterial and anticanceractivity on the one hand, and hemolysis of red blood cells on the other.

[0002] The growing problem of microbial resistance to establishedantibiotics has stimulated intense interest in developing novelantimicrobial agents with new modes of action (H. Breithaupt, Nat.Biotechnol. 1999, 17, 1165-1169). One emerging class of antibiotics isbased on naturally occurring cationic peptides (T. Ganz, R. L. Lehrer,Mol. Medicine Today 1999, 5, 292-297; R. M. Epand, H. J. Vogel, Biochim.Biophys. Acta 1999, 1462, 11-28). These include disulfide-bridgedβ-hairpin and β-sheet peptides (such as the protegrins [V. N. M.; O. V.Shamova, H. A. Korneva, R. I. Lehrer, FEBS Lett. 1993, 327, 231-236],tachyplesins [T. Nakamura, H. Furunaka, T. Miyata, F. Tokunaga, T. Muta,S. Iwanaga, M. Niwa, T.

[0003] Takao, Y. Shirnonishi, Y. J. Biol. Chem. 1988, 263, 16709-16713],and the defensins (R. I.

[0004] Lehrer, A. K. Lichtenstein, T. Ganz, Annu. Rev. Immunol. 1993,11, 105-128], amphipathic α-helical peptides (e.g. cecropins,dernnaseptins, magainins, and mellitins [A. Tossi, L. Sandri, A.Giangaspero, Biopolymers 2000, 55, 4-30]), as well as other linear andloop-structured peptides. Although the mechanisms of action ofantimicrobial cationic peptides are not yet fully understood, theirprimary site of interaction is the microbial cell membrane (H. W. Huang,Biochemistry 2000, 39, 8347-8352). Upon exposure to these agents, thecell membrane undergoes permeabilization, which is followed by rapidcell death. However, more complex mechanisms of action, for example,involving receptor-mediated signaling; cannot presently be ruled out (M.Wu, E. Maier, R. Benz, R. E. Hancock, Biochemistry 1999, 38, 7235-7242).

[0005] The antimicrobial activities of many of these cationic peptidesusually correlate with their preferred secondary structures, observedeither in aqueous solution or in membrane-like environments (N. Sitaram,R. Nagaraj, Biochim. Biophys. Acta 1999, 1462, 29-54). Structuralstudies by nuclear magnetic resonance (NMR) spectroscopy have shown thatcationic peptides such as protegrin 1 (A. Aumelas, M. Mangoni, C.Roumestand, L. Chiche, E. Despaux, G. Grassy, B. Calas, A. Chavanieu, A.Eur. J. Biochem. 1996, 237, 575-583; R. L. Fahrner, T. Dieckmann, S. S.L. Harwig, R. I. Lehrer, D. Eisenberg, J. Feigon, J. Chem. Biol. 1996,3, 543-550) and tachyplesin I (K. Kawano, T. Yoneya, T. Miyata, K.Yoshikawa, F. Tokunaga, Y. Terada, S. J. Iwanaga, S. J. Biol. Chem.1990, 265, 15365-15367) adopt well defined β-hairpin conformations, dueto the constraining effect of two disulfide bridges. In protegrinanalogues lacking one or both of these disulfide bonds, the stability ofthe β-hairpin conformation is dirinished, and the antimicrobial activityis reduced (J. Chen, T. J. Falla, H. J. Liu, M. A. Hurst, C. A. Fujii,D. A. Mosca, J. K EmbreeD. J. Loury, P. A. Radel, C. C. Chang, L. Gu, J.C. Fiddes, Biopolymers 2000, 55, 88-98; S. L. Harwig, A. Waring, H. J.Yang, Y. Cho, L. Tan, R. I. Lehrer, R. J. Eur. J. Biochein. 1996, 240,352-357; M. E. Mangoni, A. Aumelas, P. Charnet, C. Roumestand, L.Chiche, E. Despaux, G. Grassy, B. Calas, A. Chavanieu, FEBS Lett. 1996,383, 93-98; H. Tamamura, T. Murakami, S. Noriuchi, K. Sugihara, A.Otaka, W. Takada, T. Ibuka, M. Waki, N. Tamamoto, N. Fujii, Chem. Pharm.Bull. 1995, 43, 853-858). Similar observations have been made inanalogues of tachyplesin I (H. Tamamura, R. Ikoma, M. Niwa, S.Funakoshi, T. Murakami, N. Fujii, Chem. Pharm. Bull. 1993, 41, 978-980)and in hairpin-loop mimetics of rabbit defensin NP-2 (S.Thennarasu, R.Nagaraj, Biochem. Biophys. Res. Comm. 1999, 254, 281-283). These resultsshow that the β-hairpin structure plays an important role in theantimicrobial activity and stability of these protegrin-like peptides.In the case of the cationic peptides preferring α-helical structures,the amphililic structure of the helix appears to play a key role indetermining antimicrobial activity (A. Tossi, L. Sandri, A. Giangaspero,A. Biopolymers 2000, 55, 430). Gramicidin S is a backbone-cyclic peptidewith a well defined β-hairpin structure (S. E. Hull, R. Karlsson, P.Main, M. M. Woolfson, E. J. Dodson, Nature 1978, 275, 206-275) thatdisplays potent antimicrobial activity against gram-positive andgram-negative bacteria (L. H. Kondejewski, S. W. Farmer, D. S. Wishart,R. E. Hancock, R. S. Hodges, Int. J. Peptide Prot. Res. 1996,47,460-466). The high hemolytic activity of gramicidin S has, however,hindered its widespread use as an antibiotic. Recent structural studiesby NMR have indicated that the high hemolytic activity apparentlycorrelates with the highly amphipathic nature of this cyclicβ-hairpin-like molecule, but that it is possible to dissociateantimicrobial and hemolytic activities by modulating the conformationand amphiphilicity (L. H. Kondejewski, M. Jelokhani-Niarali, S. W.Farmer, B. Lix, M. Kay, B. D. Sykes, R. E. Hancock, R. S. Hodges, J.Biol. Chem. 1999, 274, 13181-13192; C. McInnesL. H. Kondejewski, R. S.Hodges, B. D. Sykes, J. Biol. Chem. 2000, 275, 14287-14294).

[0006] A new cyclic antimicrobial peptide RTD-1 was reported recentlyfrom primate leukocytes (Y.-Q. Tang, J. Yuan, G. Ösapay, K. Ösapay, D.Tran, C. J. Miller, A. J. Oellette, M. E. Selsted, Science 1999, 286,498-502. This peptide contains three disulfide bridges, which act toconstrain the cyclic peptide backbone into a hairpin geometry. Cleavageof the three disulfide bonds leads to a significant loss ofantimicrobial activity. Analogues of protegrins (J. P. Tam, C. Wu, J.-L.Yang, Eur. J. Biochem. 2000, 267, 3289-3300) and tachyplesins (J.-P.Tam, Y.-A. Lu, I.-L. Yang, Biochemistry 2000, 39, 7159-7169; N. Sitaram,R. Nagaraij, Biochem. Biophys. Res. Comm. 2000, 267, 783-790) containinga cyclic peptide backbone, as well as multiple disulfide bridges toenforce a amphiphilic hairpin structure, have also been reported. Inthese cases, removal of all the cystine constraints does not always leadto a large loss of antimicrobial activity, but does modulate themembranolytic selectivity (J. P. Tam, C. Wu, J.-L. Yang, Eur. J.Biochem. 2000, 267, 3289-3300).

[0007] A key issue in the design of new cationic antimicrobial peptidesis selectivity. The naturally occurring protegrins and tachyplesinsexert a significant hemolytic activity against human red blood cells.This is also the case for protegrin analogues such as IB367 (J. Chen, T.J. Falla, H. J. Liu, M. A. Hurst, C. A. Fujii, D. A. Mosca, J. R Embree,D. J. Loury, P. A. Radel, C. C. Chang, L. Gu, J. C. Fiddes, Biopolymers2000, 55, 88-98; C. Chang, L. Gu, J. Chen, U.S. Pat. No. 5,916,872,1999). This high hemolytic activity essentially obviates its use invivo, and represents a serious disadvantage in clinical applications.Also, the antibiotic activity of analogues often decreases significantlywith increasing salt concentration, such that under in vivo conditions(ca. 100-150 mM NaCl) the antimicrobial activity may be severelyreduced. Before intravenous use can be considered, the general toxicity,protein-binding activity in blood serum, as well as protease stabilitybecome serious issues which must be adequately addressed.

[0008] Protegrin 1 exhibits potent and similar activity againstgram-positive and gram-negative bacteria as well as fungi in both low-and high-salt assays. This broad antimicrobial activity combined with arapid mode of action, and their ability to kill bacteria resistant toother classes of antibiotics, make them attractive targets fordevelopment of clinically useful antibiotics. The activity againstgram-positive bacteria is typically higher than against gram-negativebacteria. However, protegrin 1 also exhibits a high hemolytic activityagainst human red blood cells, and hence a low selectivity towardsmicrobial cells. Oriented CD experiments (W. T. Heller, A. J. Waring, R.I. Lehrer, H. W. Huang, Biochemistry 1998, 37, 17331-17338) indicatethat protegrin 1 may exist in two different states as it interacts withmembranes, and these states are strongly influenced by lipidcomposition. Studies of cyclic protegrin analogues (J.-P. Tam, C. Wu,J.-L. Yang, Eur. J. Biochem. 2000, 267, 3289-3300) have revealed, thatan increase in the conformational rigidity, resulting from backbonecyclization and multiple disulfide bridges, may confer membranolyticselectivity that dissociates antimicrobial activity from hemolyticactivity, at least in the series of compounds studied. Protegrin 1 is an18 residues linear peptide, with an amidated carboxyl terminus and twodisulfide bridges. Tachyplesin I contains 17 residues, also has anamidated carboxyl terminus and contains two disulfide bridges. Recentlydescribed backbone-cyclic protegrin and tachyplesin analogues typicallycontain 18 residues and up to three disulfide bridges (J. P. Tam, C. Wu,J.-L. Yang, Eur. J. Biochem. 2000, 267, 3289-3300; J. P. Tam, Y.-A. Lu,J.-L. Yang, Biochemistry 2000, 39, 7159-7169; N. Sitaram, R. Nagaraij,Biochem. Biophys. Res. Comm. 2000, 267, 783-790).

[0009] Cathelicidin, a 37-residue linear helical-type cationic peptide,and analogues are currently under investigation as inhaled therapeuticagents for cystic fibrosis (CF) lung disease (. Saiman, S. Tabibi, T. D.Starner, P. San Gabriel, P. L. Winokur, H. P. Jia, P. B. McGray, Jr., B.F. Tack, Antimicrob. Agents and Chemother. 2001, 45, 2838-2844; R. E. W.Hancock, R. Lehrer, Trends Biotechnol. 1998, 16, 82-88). Over 80% of CFpatients become chronically infected with pseudomonas aeruginosa (C. A.Demko, P. J. Biard, P. B. Davies, J. Clin. Epidemiol. 1995, 48,1041-1049; E. M. Kerem, R Gold, H. Levinson, J. Pediatr. 1990, 116,714-719).

[0010] In addition, there is evidence from the literature that somecationic peptides exibit interesting anticancer activity. Cerecropin B,a 35-residue α-helical cationic peptide isolated from the hemolymph ofthe giant silk moth, and shorter analogues derived from Cerecropin Bhave been investigated as potential anticancer compounds (A. J. Moore,D. A. Devine, M. C. Bibby, Peptide Research 1994, 7, 265-269).

[0011] In the compounds described below, a new strategy is introduced tostabilize β-hairpin conformations in backbone-cyclic cationic peptidemimetic exhibiting antimicrobial and anticancer activity. This involvestransplanting the cationic and hydrophobic hairpin sequence onto atemplate, whose function is to restrain the peptide loop backbone into ahairpin geometry. The rigidity of the hairpin may be further influencedby introducing a disulfide bridge. The template moiety may also act asan attachment point for other organic groups, that may modulate theantimicrobial and/or membranolytic targeting selectivity of themolecule, and be useful for producing dimeric species, where thetemplates in each monomer unit are linked through a short spacer orlinker. Template-bound hairpin mimetic peptides have been described inthe literature (D, Obrecht, M. Altorfer, J. A. Robinson, Adv. Med. Chem.1999, 4, 168; J. A. Robinson, Syn. Lett. 2000, 4, 429-441), but suchmolecules have not previously been evaluated for development ofantimicrobial peptides. However, the ability to generate β-hairpinpeptidomimetics using combinatorial and parallel synthesis methods hasnow been established (L. Jiang, K. Moehle, B. Dhanapal, D. Obrecht, J.A. Robinson, Helv. Chim. Actia. 2000, 83, 3097-3112).

[0012] These methods allow the synthesis and screening of large hairpinmimetic libraries, which in turn considerably facilitatesstructure-activity studies, and hence the discovery of new moleculeswith potent antimicrobial and anticancer activity and low hemolyticactivity to human red blood cells. Furthermore, the present strategyallows to synthesize β-hairpin peptidomimetics with novel selectivitiestowards different types of pathogens, e.g. towards various multi-rugresistant pseudomonas strains. β-Hairpin peptidomimetics obtained by theapproach described here can be used amongst other applications, e.g. asbroad spectrum antibiotics, as therapeutics for cystic fibrosis lungdisease and anticancer agents.

[0013] The β-hairpin peptidomimetics of the present invention arecompounds of the general formulae

[0014] wherein

[0015] is a group of one of the formulae

[0016] wherein

[0017] is the residue of an L-α-amino acid with B being a residue offormula —NR²⁰CH(R⁷¹)— or the enantiomer of one of the groups A1 to A69as defined hereinafter;

[0018] is a group of one of the formulae

[0019] R¹ is H; lower alkyl; or aryl-lower allyl;

[0020] R² is H; allyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;—(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or—(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;

[0021] R³ is H; allyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;—(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(s)R³³R³⁴;—(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or—(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;

[0022] R⁴ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;—(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(p)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(p)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(p)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or—(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;

[0023] R⁵ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;—(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or—(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;

[0024] R⁶ is H; alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;—(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or—(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;

[0025] R⁷ is alkyl; alkenyl; —(CH₂)_(q)(CHR⁶¹)_(s)OR⁵⁵;—(CH₂)_(q)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(q)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(q)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(r)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(r)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(r)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(r)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(r)(CHR⁶¹)_(s)C₆H₄R⁸;

[0026] R⁸ is H; Cl; F; CF₃; NO₂; lower alkyl; lower alkenyl; aryl;aryl-lower alkyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)COR⁶⁴;

[0027] R⁹ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;—(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or—(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;

[0028] R¹⁰ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;—(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or—(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;

[0029] R¹¹ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;—(CH₂)_(m)(CHR⁶¹)_(s)R³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁶⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₅H₄R⁸;

[0030] R⁸² is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;—(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(r)CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(r)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(r)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(r)(CHR⁶¹)_(s)SO₂R⁶²; or—(CH₂)_(r)CHR⁶¹)_(s)C₆H₄R⁸;

[0031] R¹³ is alkyl; alkenyl; —(CH₂)_(q)(CHR⁶¹)_(s)OR⁵⁵;—(CH₂)_(q)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(q)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(q)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(q)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(q)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(q)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(q)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(q)(CHR⁶¹)_(s)SO₂R⁶²; or—(CH₂)_(q)(CHR⁶¹)_(s)C₆H₄R⁸;

[0032] R¹⁴ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;—(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(q)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(q)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(q)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(q)(CHR⁶¹)_(s)SOR⁶²; or —(CH₂)_(q)(CHR⁶¹)_(s)C₆H₄R⁸;

[0033] R¹⁵ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;—(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(p)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(p)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(q)(CHR⁶¹)_(s) SO₂R⁶²; or—(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;

[0034] R¹⁶ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;—(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or—(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;

[0035] R¹⁷ is alkyl; alkenyl; —(CH₂)_(q)(CHR⁶¹)_(s)OR⁵⁵;—(CH₂)_(q)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(q)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(q)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(q)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(q)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(q)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(q)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(q)(CHR⁶¹)_(s)SO₂R⁶²; or—(CH₂)_(q)(CHR⁶¹)_(s)C₆H₄R⁸;

[0036] R¹⁸ is alkyl; alkenyl; —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵;—(CH₂)_(p)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(p)(CHR⁶¹)_(s)R³³R³⁴;—(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(p)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(p)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(p)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or—(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;

[0037] R¹⁹ is lower alkyl; —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵;—(CH₂)_(p)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(p)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(p)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(p)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or—(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; or

[0038] R¹⁸ and R¹⁹ taken together can form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;

[0039] R²⁰ is H; alkyl; alkenyl; or aryl-lower alkyl;

[0040] R²¹ is H; alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;—(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or—(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;

[0041] R²² is H; alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;—(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(m)(CHR⁶¹)_(s)SO₂R⁶²; or—(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;

[0042] R²³ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;—(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or—(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;

[0043] R²⁴ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;—(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(o)(CHR⁶¹))_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or—(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;

[0044] R²⁵ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;—(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or—(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;

[0045] R²⁶ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;—(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or—(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; or

[0046] R²⁵ and R²⁶ taken together can form: —(CH₂)₂₋₆—;—(CH₂)_(r)O(CH₂)_(r)—; —(CH₂)_(r)S(CH₂)_(r)—; or—(CH₂)_(r)R⁵⁷(CH₂)_(r)—;

[0047] R²⁷ is H; alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;—(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁵)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or—(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;

[0048] R²⁸ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)—OR⁵⁵;—(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or—(CH₂)_(s)(CHR⁶¹)_(s)C₆H₄R⁸;

[0049] R²⁹ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;—(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s) SO₂R⁶²; or—(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;

[0050] R³⁰ is H; alkyl; alkenyl; or aryl-lower alkyl;

[0051] R³¹ is H; alkyl; alkenyl; —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵;—(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;

[0052] R³² is H; lower alkyl; or aryl-lower alkyl;

[0053] R³³ is H; alkyl, alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;—(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴R⁶³; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR⁷⁵R⁸²;—(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR⁷⁸R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COR⁶⁴;—(CH₂)_(o)(CHR⁶¹)_(s)—CONR⁵⁸R⁵⁹, —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;

[0054] R³⁴ is H; lower alkyl; aryl, or aryl-lower alkyl;

[0055] R³³ and R³⁴ taken together can form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;

[0056] R³⁵ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;—(CH₂)_(m)(CHR⁶¹)_(s)R³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)CONR³³R⁷⁵;—(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(p)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(p)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(p)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;

[0057] R³⁶ is H, alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;—(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(p)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(p)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(p)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;

[0058] R³⁷ is H; F; Br, Cl; NO₂; CF₃; lower alkyl;—(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(p)(CH₆₁)_(s)NR³³R³⁴;—(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or—(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;

[0059] R³⁸ is H; F; Br; Cl; NO₂; CF₃; alkyl; alkenyl;—(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or—(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;

[0060] R³⁹ is H; alkyl; alkenyl; or aryl-lower alkyl;

[0061] R⁴⁰ is H; alkyl; alkenyl; or aryl-lower alkyl;

[0062] R⁴¹ is H; F; Br; Cl; NO₂; CF₃; alkyl; alkenyl;—(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or—(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;

[0063] R⁴² is H; F; Br, Cl; NO₂; CF₃; alkyl; alkenyl;—(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³⁵R⁸²;—(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or—(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;

[0064] R⁴³ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;—(CH₂)_(m)(CHR⁶¹)_(s)NR³³R⁸²; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;

[0065] R⁴⁴ is alkyl; alkenyl; —(CH₂)_(r)(CHR⁶¹)_(s)OR⁵⁵;—(CH₂)_(r)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(r)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(r)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(r)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(r)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(r)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(r)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(r)(CHR⁶¹)_(s)SO₂R⁶²; or—(CH₂)_(r)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;

[0066] R⁴⁵ is H; alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;—(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH²)_(s)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(s)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(s)(CHR⁶¹)_(s)SO₂R⁶²; or—(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;

[0067] R⁴⁶ is H; alkyl; alkenyl; or —(CH₂)_(o)(CHR⁶¹)_(p)C₆H₄R⁸;

[0068] R⁴⁷ is H; alkyl; alkenyl; or —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;

[0069] R⁴⁸ is H; lower alkyl; lower alkenyl; or aryl-lower alkyl;

[0070] R⁴⁹ is H; alkyl; alkenyl; —(CHR⁶¹)_(s)COOR⁵⁷;(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; (CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CHR⁶¹)_(s)SOR⁶²; or—(CHR⁶¹)_(s)C₆H₄R⁸;

[0071] R⁵⁰ is H; lower alkyl; or aryl-lower allyl;

[0072] R⁵⁷ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;—(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(o)(CHR⁶¹)_(p)PO(OR⁶⁰)₂; —(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or—(CH₂)_(p)(CHR⁶¹)_(s)C₆H₄R⁸;

[0073] R⁵² is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;—(CH₂)—(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R³⁴;—(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(o)(CHR⁶¹)_(p)PO(OR⁶⁰)₂; —(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or—(CH₂)_(p)(CHR⁶¹)_(s)C₆H₄R⁸;

[0074] R⁵³ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;—(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(o)(CHR⁶¹)_(p)PO(OR⁶⁰)₂; —(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or—(CH₂)_(p)(CHR⁶¹)_(s)C₆H₄R⁸;

[0075] R⁵⁴ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;—(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;

[0076] R⁵⁵ is H; lower alkyl; lower alkenyl; aryl-lower alkyl;—(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁷; —(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴R⁶³;—(CH₂)_(m)(CHR⁶¹)_(s)OCONR⁷⁵R⁸²; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR⁷⁸R⁸²;—(CH₂)_(o)(CHR⁶¹)_(s)—COR⁶⁴; —(CH₂)_(o)(CHR⁶¹)COOR⁵⁷; or—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;

[0077] R⁵⁶ is H; lower alkyl; lower alkenyl; aryl-lower allyl;—(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁷; —(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴R⁶³;—(CH₂)_(m)(CHR⁶¹)_(s)OCONR⁷⁵R⁸²; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR⁷⁸R⁸²;—(CH₂)_(o)(CHR⁶¹)_(s)—COR⁶⁴; or —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;

[0078] R⁵⁷ is H; lower alkyl; lower alkenyl; aryl lower alkyl; orheteroaryl lower alkyl;

[0079] R⁵⁸ is H; lower alkyl; lower alkenyl; aryl; heteroaryl;aryl-lower alkyl; or heteroaryl-lower alkyl;

[0080] R⁵⁹ is H; lower alkyl; lower alkenyl; aryl; heteroaryl;aryl-lower alkyl; or heteroaryl-lower alkyl; or

[0081] R⁵⁸ and R⁵⁹ taken together can form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;

[0082] R⁶⁰ is H; lower alkyl; lower alkenyl; aryl; or aryl-lower alkyl;

[0083] R⁶¹ is alkyl; alkenyl; aryl; heteroaryl; aryl-lower alkyl;heteroaryl-lower alkyl; —(CH₂)_(m)OR⁵⁵; —(CH₂)_(m)NR³³R³⁴;—(CH₂)_(m)NR²⁰CONR⁷⁸R⁸²; —(CH₂)_(o)COOR³⁷; —(CH₂)_(o)R⁵⁸R⁵⁹; or—(CH₂)_(o)PO(COR⁶⁰)₂;

[0084] R⁶² is lower alkyl; lower alkenyl; aryl, heteroaryl; oraryl-lower alkyl;

[0085] R⁶³ is H; lower alkyl; lower alkenyl; aryl, heteroaryl;aryl-lower alkyl; heteroaryl-lower alkyl; —COR⁶⁴; —COOR⁵⁷; —CONR⁵⁸R⁵⁹;—SO₂R⁶²; or —PO(OR⁶⁰)₂;

[0086] R³⁴ and R⁶³ taken together can form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;

[0087] R⁶⁴ is H; lower alkyl; lower alkenyl; aryl; heteroaryl;aryl-lower alkyl; heteroaryl-lower alkyl; —(CH₂)_(p)(CHR⁶¹)_(s)OR⁶⁵;—(CH₂)_(p)(CHR⁶¹)_(s)SR⁶⁶; or —(CH₂)_(p)(CHR⁶¹)_(s)NR³⁴R⁶³;—(CH₂)_(p)(CHR⁶¹)_(s)OCONR⁷⁵R⁸²; —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR⁷⁸R⁸²;

[0088] R⁶⁵ is H; lower alkyl; lower alkenyl; aryl, aryl-lower alkyl;heteroaryl-lower alkyl; —COR⁵⁷; —COOR⁵⁷; or —CONR⁵⁸R⁵⁹;

[0089] R⁶⁵ is H; lower alkyl; lower alkenyl; aryl; aryl-lower alkyl;heteroaryl-lower alkyl; or —CONR⁵⁸R⁵⁹;

[0090] m is 2-4; o is 0-4; p is 1-4; q is 0-2; r is 1 or 2; s is 0 or 1;

[0091] independently have any of the significances defined above for

[0092] except (a1) or (a2) with B being —NR²⁰CH(R⁷¹)— and with A beingA80, A81, A90, A91, A95 or A96, and except (f) and (m), but wherein

[0093] R² is —(CH₂)_(m)(CHR⁶¹)_(s)O—; —(CH₂)_(m)(CHR⁶¹)_(s)S—;—(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴—; or —(CH₂)_(o)(CHR⁶¹)_(s)CO—;

[0094] R³ is —(CH₂)_(m)(CHR⁶¹)_(s)O—; —(CH₂)_(m)(CHR⁶¹)_(s)S—;—(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴—; or —(CH₂)_(o)(CHR⁶¹)_(s)CO—;

[0095] R⁴ is —(CH₂)_(m)(CHR⁶¹)_(s)O—; —(CH₂)_(m)(CHR⁶¹)_(s)S—;—(CH₂)_(m)(CHR⁶¹)_(s)NR³—; or —(CH₂)_(p)(CHR⁶¹)_(s)CO—;

[0096] R⁵ is —(CH₂)_(o)(CHR⁶¹)_(s)O—; —(CH₂)_(o)(CHR⁶¹)_(s)S—;—(CH₂)_(o)(CHR⁶¹)_(s)NR³⁴—; or —(CH₂)_(o)(CHR⁶¹)_(s)CO—;

[0097] R⁶ is —(CH₂)_(o)(CHR⁶¹)_(s)O—; —(CH₂)_(o)(CHR⁶¹)_(s)S—;—(CH₂)_(o)(CHR⁶¹)_(s)NR³⁴—; or —(CH₂)_(o)(CHR⁶¹)_(s)CO—;

[0098] R⁷ is —(CH₂)_(q)(CHR⁶¹)_(s)O—; —(CH₂)_(q)(CHR⁶¹)_(s)NR³⁴; or—(CH₂)_(r)(CHR⁶¹)_(s)CO—;

[0099] R⁸ is —(CH₂)_(o)(CHR⁶¹)_(s)O—; —(CH₂)_(o)(CHR⁶¹)_(s)S—;—(CH₂)_(o)(CHR⁶¹)_(s)NR³⁴—; or —(CH₂)_(o)(CHR⁶¹)_(s)CO—;

[0100] R⁹ is —(CH₂)_(o)(CHR⁶¹)_(s)O—; —(CH₂)_(o)(CHR⁶¹)_(s)S—;—(CH₂)_(o)(CHR⁶¹)_(s)NR³⁴—; or —(CH₂)_(o)(CHR⁶¹)_(s)CO—;

[0101] R¹⁰ is —(CH₂)_(o)(CHR⁶¹)_(s)O—; —(CH₂)_(o)(CHR⁶¹)_(s)S—;—(CH₂)_(o)(CHR⁶¹)_(s)NR³⁴—; or —(CH₂)_(o)(CHR⁶¹)_(s)CO—;

[0102] R¹¹ is —(CH₂)_(m)(CHR⁶¹)_(s)O—; —(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴—; or—(CH₂)_(o)(CHR⁶¹)_(s)CO—;

[0103] R¹² is —(CH₂)_(m)(CHR⁶¹)_(s)O—, —(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴—; or—(CH₂)_(r)(CHR⁶¹)_(s)CO—;

[0104] R¹³ is —(CH₂)_(q)(CHR⁶¹)_(s)O—; —(CH₂)_(q)(CHR⁶¹)_(s)S—;—(CH₂)_(q)(CHR⁶¹)_(s)NR³⁴—; or —(CH₂)_(q)(CHR⁶¹)_(s)CO—;

[0105] R¹⁴ is —(CH₂)_(m)(CHR⁶¹)_(s)O—; —(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴—; or—(CH₂)_(q)(CHR⁶¹)_(s)CO—;

[0106] R¹⁵ is —(CH₂)_(o)(CHR⁶¹)_(s)O—; —(CH₂)_(o)(CHR⁶¹)_(s)S—;—(CH₂)_(o)(CHR⁶¹)_(s)NR³⁴—; or —(CH₂)_(o)(CHR⁶¹)_(s)CO—;

[0107] R¹⁶ is —(CH₂)_(o)(CHR⁶¹)_(s)O—; —(CH₂)_(o)(CHR⁶¹)_(s)S—;—(CH₂)_(o)(CHR⁶¹)_(s)NR³⁴—; or —(CH₂)_(p)(CHR⁶¹)_(s)CO—;

[0108] R¹⁷ is —(CH₂)_(q)(CHR⁶¹)_(s)O—; —(CH₂)_(q)(CHR⁶¹)_(s)S—;—(CH₂)_(q)(CHR⁶¹)_(s)NR³⁴—; or —(CH₂)_(q)(CHR⁶¹)_(s)CO—;

[0109] R¹⁸ is —(CH₂)_(p)(CHR⁶¹)_(s)O—; —(CH₂)_(p)(CHR⁶¹)_(s)S—;—(CH₂)_(p)(CHR⁶¹)_(s)NR³⁴—; or —(CH₂)_(p)(CHR⁶¹)_(s)CO—;

[0110] R¹⁹ is —(CH₂)_(p)(CHR⁶¹)_(s)O—; —(CH₂)_(p)(CHR⁶¹)_(s)S—;—(CH₂)_(p)(CHR⁶¹)_(s)NR³⁴—; or —(CH₂)_(p)(CHR⁶¹)_(s)CO—;

[0111] R²¹ is —(CH₂)_(o)(CHR⁶¹)_(s)O—; —(CH₂)_(o)(CHR⁶¹)_(s)S—;—(CH₂)_(o)(CHR⁶¹)_(s)NR³⁴—; or —(CH₂)_(o)(CHR⁶¹)_(s)CO—;

[0112] R²² is —(CH₂)_(o)(CHR⁶¹)_(s)O—; —(CH₂)_(o)(CHR⁶¹)_(s)S—;—(CH₂)_(o)(CHR⁶¹)_(s)NR³⁴—; or —(CH₂)_(o)(CHR⁶¹)_(s)CO—;

[0113] R²³ is —(CH₂)_(o)(CHR⁶¹)_(s)O; —(CH₂)_(o)(CHR⁶¹)_(s)S—;—(CH₂)_(o)(CHR⁶¹)_(s)NR³⁴—; or —(CH₂)_(o)(CHR⁶¹)_(s)CO—;

[0114] R²⁴ is —(CH₂)_(o)(CHR⁶¹)_(s)O; —(CH₂)_(o)(CHR⁶¹)_(s)S—;—(CH₂)_(o)(CHR⁶¹)_(s)NR³⁴—; or —(CH₂)_(o)(CHR⁶¹)_(s)CO—;

[0115] R²⁵ is —(CH₂)_(m)(CHR⁶¹)_(s)O—; —(CH₂)_(m)(CHR⁶¹)_(s)S—;—(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴—; or —(CH₂)_(o)(CHR⁶¹)_(s)CO—;

[0116] R²⁶ is —(CH₂)_(m)(CHR⁶¹)_(s)O—; —(CH₂)_(m)(CHR⁶¹)_(s)S—;—(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴—; or —(CH₂)_(o)(CHR⁶¹)_(s)CO—;

[0117] R²⁷ is —(CH₂)_(o)(CHR⁶¹)_(s)O—; —(CH₂)_(o)(CHR⁶¹)_(s)S—,—(CH₂)_(o)(CHR⁶¹)_(s)NR³⁴—; or —(CH₂)_(o)(CHR⁶¹)_(s)CO—;

[0118] R²⁸ is —(CH₂)_(m)(CHR⁶¹)_(s)O—; —(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴; or—(CH₂)_(o)(CHR⁶¹)_(s)CO—;

[0119] R²⁹ is —(CH₂)_(o)(CHR⁶¹)_(s)O—; —(CH₂)_(o)(CHR⁶¹)_(s)S—;—(CH₂)_(o)(CHR⁶¹)_(s)R³⁴—; or —(CH₂)_(o)(CHR⁶¹)_(s)CO—;

[0120] R³¹ is —(CH₂)_(p)(CHR⁶¹)_(s)O—; —(CH₂)_(p)(CHR⁶¹)_(s)S—;—(CH₂)_(p)(CHR⁶¹)_(s)NR³⁴—; or —(CH₂)_(o)(CHR⁶¹)_(s)CO—;

[0121] R³³ is —(CH₂)_(m)(CHR⁶¹)_(s)O—; —(CH₂)_(m)(CH₂)_(s)NR³⁴—; or—(CH₂)_(o)(CHR⁶¹)_(s)CO—;

[0122] R³⁷ is —(CH₂)_(p)(CHR⁶¹)_(s)O—; —(CH₂)_(p)(CHR⁶¹)_(s)S—;—(CH₂)_(p)(CHR⁶¹)_(s)NR³⁴—; or —(CH₂)_(o)(CHR⁶¹)_(s)CO—;

[0123] R³⁸ is —(CH₂)_(p)(CHR⁶¹)_(s)O—; —(CH₂)_(p)(CHR⁶¹)_(s)S—;—(CH₂)_(p)(CHR⁶¹)_(s)NR³⁴—; or —(CH₂)_(o)(CHR⁶¹)_(s)CO—;

[0124] R⁴¹ is —(CH₂)_(p)(CHR⁶¹)_(s)O—; —(CH₂)_(p)(CHR⁶¹)_(s)S—;—(CH₂)_(p)(CHR⁶¹)_(s)NR³⁴—; or —(CH₂)_(o)(CHR⁶¹)_(s)CO—;

[0125] R⁴² is —(CH₂)_(p)(CHR⁶¹)_(s)O—; —(CH₂)_(p)(CHR⁶¹)_(s)S—;—(CH₂)_(p)(CHR⁶¹)_(s)NR³⁴—; or —(CH₂)_(o)(CHR⁶¹)_(s)CO—;

[0126] R⁴³ is —(CH₂)_(m)(CHR⁶¹)_(s)O; —(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴—; or—(CH₂)_(o)(CHR⁶¹)_(s)CO—;

[0127] R⁴⁵ is —(CH₂)_(o)(CHR⁶¹)_(s)O—; —(CH₂)_(o)(CHR⁶¹)_(s)S—;—(CH₂)_(o)(CHR⁶¹)_(s)NR³⁴—; or —(CH₂)_(s)(CHR⁶¹)_(s)CO—;

[0128] R⁴⁷ is —(CH₂)_(o)(CHR⁶¹)_(s)O—;

[0129] R⁴⁹ is —(CHR⁶¹)_(s)O—; —(CHR⁶¹)_(s)S—; —(CHR⁶¹)_(s)NR³⁴—; or—(CHR⁶¹)_(s)CO—;

[0130] R⁵¹ is —(CH₂)_(m)(CHR⁶¹)_(s)O—; —(CH₂)_(m)(CHR⁶¹)_(s)S—;—(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴—; or —(CH₂)_(o)(CHR⁶¹)_(s)CO—;

[0131] R⁵² is —(CH₂)_(m)(CHR⁶¹)_(s)O—; —(CH₂)_(m)(CHR⁶¹)_(s)S—;—(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴—; or —(CH₂)_(o)(CHR⁶¹)_(s)CO—;

[0132] R⁵³ is —(CH₂)_(m)(CHR⁶¹)_(s)O—; —(CH₂)_(m)(CHR⁶¹)_(s)S;—(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴—; or —(CH₂)_(o)(CHR⁶¹)_(s)CO—;

[0133] R⁵⁴ is —(CH₂)_(m)(CHR⁶¹)_(s)O—; —(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴—; or—(CH₂)_(o)(CHR⁶¹)_(s)CO—;

[0134] R⁵⁵ is —(CH₂)_(m)(CHR⁶¹)_(s)O—; —(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴—; or—(CH₂)_(o)(CHR⁶¹)_(s)CO—;

[0135] R⁵⁶ is —(CH₂)_(m)(CHR⁶¹)_(s)O—; —(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴—; or—(CH₂)_(o)(CHR⁶¹)_(s)CO—;

[0136] R⁶⁴ is —(CH₂)_(p)(CHR⁶¹)_(s)O—; —(CH₂)_(p)(CHR⁶¹)_(s)S—; or—(CH₂)_(p)(CHR⁶¹)_(s)NR³⁴—;

[0137] m, o, p, q, r and s being as defined above;

[0138] with the proviso that if more than one of the substituents R² toR¹⁹, R²¹ to R¹⁹, R³¹, R³³, R³⁷, R³⁸, R⁴¹ to R⁴³, R⁴⁵, R⁴⁷, R⁴⁹, R⁵¹ toR⁵⁶ and R⁶⁴ is present, only one of these has one of the significancesjust mentioned whilst the other(s) haslhave any of the significance(s)mentioned earlier;

[0139] L is a direct bond or one of the linkers

[0140] L1: —(CH₂)_(p)CHR⁶¹[X(CH₂)_(p)CHR⁶¹]_(o)—;

[0141] L2: —CO(CH₂)_(p)CHR⁶¹[X(CH₂)_(p)CHR⁶¹]_(o)CO—;

[0142] L3: —CONR³⁴(CH₂)_(p)CHR⁶¹]X(CH₂)_(p)CHR⁶¹]_(o)NR³⁴CO—;

[0143] L4: —O(CH₂)_(p)CHR⁶¹[X(CH₂)pCHR⁶¹]_(O)O—;

[0144] L5: —S(CH₂)_(p)CHR⁶¹[X(CH₂)pCHR⁶¹]_(o)S—;

[0145] L6: —NR³⁴(CH₂)_(p)CHR⁶¹[X(CH₂)pCHR⁶¹]_(o)NR³⁴—;

[0146] L7: —(CH₂)_(o)CHR⁶¹Y(CH₂)_(o)CHR⁶¹—;

[0147] L8: —CO(CH₂)_(o)CHR⁶¹Y(CH₂)_(o)CHR⁶¹CO—;

[0148] L9: —CONR³⁴(CH₂)_(o)CHR⁶¹Y(CH₂)_(o)CHR⁶¹NR³⁴CO—;

[0149] L10: —O(CH₂)_(o)CHR⁶¹Y(CH₂)_(o)CHR⁶¹O—;

[0150] L11: —S(CH₂)_(o)CHR⁶¹Y(CH₂)_(o)CHR⁶¹S—;

[0151] L12: —NR³⁴(CH₂)_(o)CHR⁶¹Y(CH₂)_(o)CHR⁶¹NR³⁴—;

[0152] L13: —CO(CH₂)_(p)CHR⁶¹ [X(CH₂)_(p)CHM⁶¹]_(o)NR³⁴—;

[0153] L14: —CO(CH₂)_(o)CHR⁶¹Y(CH₂)_(o)CHR⁶¹NR³⁴—;

[0154] L15 —NR³⁴(CH₂)_(p)CHR⁶¹[X(CH₂)pCHR⁶¹]_(o)CO—; and

[0155] L16 —NR³⁴(CH₂)_(o)CHR⁶¹Y(CH₂)_(o)CHR⁶¹CO—;

[0156] m, o, p, q, r and s being as defined above; X being O; S; NR³⁴;—NR³²CONR³⁴—; or —OCOO—;

[0157] and Y being —C⁶⁷R⁶⁸R⁶⁹R⁷⁰—;

[0158] R⁶⁷ being H; Cl; Br; F; NO₂; —NR³⁴COR⁵⁷; lower alkyl; or loweralkenyl;

[0159] R⁶ being H; Cl; Br; F; NO₂; —NR³⁴COR⁵⁷; lower alkyl; or loweralkenyl;

[0160] R⁶⁹ being H; Cl; Br; F; NO₂; —NR³⁴COR⁵⁷; lower alkyl; or loweralkenyl; and

[0161] R⁷⁰ being H; Cl; Br, F; NO₂; —NR³⁴COR⁵⁷; lower alkyl; or loweralkenyl;

[0162] with the proviso that at least two of R⁶⁷, R⁸², R⁶ and R⁷⁰ are H;and

[0163] with the further proviso that

[0164] —(CH₂)_(m)(CHR⁶¹)_(s)O— can be combined with linker L1, L2, L3,L7, L8 or L9;

[0165] —(CH₂)_(o)(CHR⁶¹)_(s)O— can be combined with linker L1, L2, L3,L7, L8 or L9;

[0166] —(CH₂)_(p)(CHR⁶¹)_(s)O— can be combined with linker L1, L2, L3,L7, L8 or L9;

[0167] —(CH₂)_(q)(CHR⁶¹)_(s)O— can be combined with linker L1, L2, L3,L7, L8 or L9;

[0168] —(CHR⁶¹)_(s)O— can be combined with linker L1, L2, L3, L7, L8 orL9;

[0169] —(CH₂)_(m)(CHR⁶¹)_(s)S— can be combined with linker L1, L2, L3,L7, L8 or L9; or can form a disulfide bond with —(CH₂)_(m)(CHR⁶¹)_(s)S—;—(CH₂)_(o)(CHR⁶¹)_(s)S—; —(CH₂)_(p)(CHR⁶¹)_(s)S—;—(CHR²)_(q)(CHR⁶¹)_(s)S—; or —(CHR⁶¹)_(s)S—;

[0170] —(CH₂)_(o)(CHR⁶¹)_(s)S— can be combined with linker L1, L2, L3,L7, L8 or L9; or can form a disulfide bond with —(CH₂)_(m)(CHR⁶¹)_(s)S—;—(CH₂)_(o)(CHR⁶¹)_(s)S—; —(CH₂)_(p)(CHR⁶¹)_(s)S—;—(CH₂)_(q)(CHR⁶¹)_(s)S—; or —(CHR⁶¹)_(s)S—;

[0171] —(CH₂)_(p)(CHR⁶¹)_(s)S— can be combined with linker L1, L2, L3,L7, L8 or L9; or can form a disulfide bond with —(CH₂)_(m)(CHR⁶¹)_(s)S—;—(CH₂)_(o)(CHR⁶¹)_(s)S—; —(CH₂)_(p)(CHR⁶¹)_(s)S—;—(CH₂)_(q)(CHR⁶¹)_(s)S—; or —(CHR⁶¹)_(s)S—;

[0172] —(CH₂)_(q)(CHR⁶¹)_(s)S— can be combined with linker L1, L2, L3,L7, L8 or L9; or can form a disulfide bond with —(CH₂)_(m)(CHR⁶¹)_(s)S—;—(CH₂)_(o)(CHR⁶¹)_(s)S—; —(CH₂)_(p)(CHR⁶¹)_(s)S—;—(CH₂)_(q)(CHR⁶¹)_(s)S—; or —(CHR⁶¹)_(s)S—;

[0173] —(CHR⁶¹)_(s)S— can be combined with linker L1, L2, L3, L7, L8 orL9; or form a disulfide bond with

[0174] —(CH₂)_(m)(CHR⁶¹)_(s)S—; —(CH₂)_(o)(CHR⁶¹)_(s)S—;—(CH₂)_(p)(CHR⁶¹)_(s)S—; —(CH₂)_(q)(CHR⁶¹)_(s)S—; or —(CHR⁶¹)_(s)S—;

[0175] —(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴— can be combined with linker L1, L2,L3, L7, L8 or L9;

[0176] —(CH₂)_(o)(CHR⁶¹)_(s)NR³⁴— can be combined with linker L1, L2,L3, L7, L8 or L9;

[0177] —(CH₂)_(p)(CHR⁶¹)_(s)NR³⁴— can be combined with linker L1, L2,L3, L7, L8 or L9;

[0178] —(CH₂)_(q)(CHR⁶¹)_(s)NR³⁴— can be combined with linker L1, L2,L3, L7, L8 or L9;

[0179] —(CHR⁶¹)_(s)NR³⁴— can be combined with linker L1, L2, L3, L7, L8or L9;

[0180] —(CH₂)_(o)(CHR⁶¹)_(s)CO— can be combined with linker L4, L5, L6,L1, L11 or L12;

[0181] —(CH₂)_(r)(CHR⁶¹)_(s)CO— can be combined with linker L4, L5, L6,L1, L11 or L12;

[0182] —(CH₂)_(q)(CHR⁶¹)_(s)CO— can be combined with linker L4, L5, L6,L10, L11 or L12;

[0183] —(CH₂)_(r)(CHR⁶¹)_(s)CO— can be combined with linker L4, L5, L6,L10, L11 or L12;

[0184] —(CHR⁶¹)_(s)CO— can be combined with linker L4, L5, L6, L10, L11or L12;

[0185] —(CH₂)_(m)(CHR⁶¹)_(s)O— can be combined with linker L13 or L14and the resulting combination with

[0186] —(CH₂)_(m)(CHR⁶¹)_(s)CO—; —(CH₂)_(o)(CHR⁶¹)_(p)CO—;—(CH₂)_(q)(CHR⁶¹)_(s)CO—; or —(CHR⁶¹)_(s)CO—;

[0187] —(CH₂)_(o)(CHR⁶¹)_(s)O— can be combined with linker L13 or L14and the resulting combination with

[0188] —(CH₂)_(o)(CHR⁶¹)_(s)CO—; —(CH₂)_(o)(CHR⁶¹)_(p)CO—;—(CH₂)_(q)(CHR⁶¹)_(s)CO—; or —(CHR⁶¹)_(s)CO—;

[0189] —(CH₂)_(p)(CHR⁶¹)_(s)CO— can be combined with linker L13 or L14and the resulting combination with

[0190] —(CH₂)_(o)(CHR⁶¹)_(s)CO—; —(CH₂)_(o)(CHR⁶¹)_(p)CO—;—(CH₂)_(q)(CHR⁶¹)_(s)CO—; or —(CHR⁶¹)_(s)CO—;

[0191] —(CH₂)_(q)(CHR⁶¹)_(s)O— can be combined with linker L13 or L14and the resulting combination with

[0192] —(CH₂)_(o)(CHR⁶³)_(s)CO—; —(CH₂)_(o)(CHR⁶¹)_(p)CO—;—(CH₂)_(q)(CHR⁶¹)_(s)CO—; or —(CHR⁶¹)_(s)O—;

[0193] —(CHR⁶¹)_(s)O— can be combined with linker L13 or L14 and theresulting combination with

[0194] —(CH₂)_(o)(CHR⁶¹)_(s)CO—; —(CH₂)_(o)(CHR⁶¹)_(p)CO—;—(CH₂)_(q)(CHR⁶¹)_(s)CO—; or —(CHR⁶¹)_(s)CO—;

[0195] —(CH₂)_(m)(CHR⁶¹)_(s)S— can be combined with linker L13 or L14and the resulting combination with

[0196] —(CH₂)_(o)(CHR⁶¹)_(s)CO—; —(CH₂)_(o)(CHR⁶¹)_(p)CO—;—(CH₂)_(q)(CHR⁶¹)_(s)CO—; or —(CHR⁶¹)_(s)CO—;

[0197] —(CH₂)_(o)(CHR⁶¹)_(s)S— can be combined with linker L13 or L14and the resulting combination with

[0198] —(CH₂)_(o)(CHR⁶¹)_(s)CO—; —(CH₂)_(o)(CHR⁶¹)_(p)CO—;—(CH₂)_(q)(CHR⁶¹)_(s)CO—; or —(CHR⁶¹)_(s)CO—;

[0199] —(CH₂)_(p)(CHR⁶¹)_(s)S— can be combined with linker L13 or L14and the resulting combination with

[0200] —(CH₂)_(o)(CHR⁶¹)_(s)CO—; —(CH₂)_(o)(CHR⁶¹)_(p)CO—;—(CH₂)_(q)(CHR⁶¹)_(s)CO—; or —(CHR⁶¹)_(s)CO—;

[0201] —(CH₂)_(q)(CHR⁶¹)_(s)S— can be combined with linker L13 or L14and the resulting combination with

[0202] —(CH₂)_(o)(CHR⁶¹)_(s)CO—; —(CH₂)_(o)(CHR⁶¹)_(s)CO—;—(CH₂)_(q)(CHR⁶¹)_(s)CO—; or —(CHR⁶¹)_(s)CO—;

[0203] —(CHR⁶¹)_(s)S— can be combined with linker L13 or L14 and theresulting combination with

[0204] —(CH₂)_(o)(CHR⁶¹)_(s)CO—; —(CH₂)_(o)(CHR⁶¹)_(p)CO—;—(CH₂)_(q)(CHR⁶¹)_(s)CO—; or —(CHR⁶¹)_(s)CO—;

[0205] —(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴— can be combined with linker L13 or L14and the resulting combination with

[0206] —(CH₂)_(o)(CHR⁶¹)_(s)CO—, —(CH₂)_(o)(CHR⁶¹)_(p)CO—;—(CH₂)_(q)(CHR⁶¹)_(s)CO—; or —(CHR⁶¹)_(s)CO—;

[0207] —(CH₂)_(o)(CHR⁶¹)_(s)NR³⁴— can be combined with linker L13 or L14and the resulting combination with

[0208] —(CH₂)_(o)(CHR⁶¹)_(s)CO—; —(CH₂)_(o)(CHR⁶¹)_(s)CO—;—(CH₂)_(q)(CHR⁶¹)_(s)CO—; or —(CHR⁶¹)_(s)CO—;

[0209] —(CH₂)_(p)(CHR⁶¹)_(s)NR³⁴— can be combined with linker L13 or L14and the resulting combination with

[0210] —(CH₂)_(o)(CHR⁶¹)_(s)CO—; —(CH₂)_(o)(CHR⁶¹)_(p)CO—;—(CH₂)_(q)(CHR⁶¹)_(s)CO—; or —(CHR⁶¹)_(s)CO—;

[0211] —(CH₂)_(q)(CHR⁶¹)_(s)NR³⁴— can be combined with linker L13 or L14and the resulting combination with

[0212] —(CH₂)_(o)(CHR⁶¹)_(s)CO—; —(CH₂)_(o)(CHR⁶¹)_(p)CO—;—(CH₂)_(q)(CHR⁶¹)_(s)CO—; or —(CHR⁶¹)_(s)CO—; —(CHR⁶¹)_(s)NR³⁴— can becombined with linker L13 or L14 and the resulting combination with

[0213] —(CH₂)_(m)(CHR⁶¹)_(s)CO—; —(CH₂)_(o)(CHR⁶¹)_(p)CO—;—(CH₂)_(q)(CHR⁶¹)_(s)CO—; or —(CHR⁶¹)_(s)CO—;

[0214] —(CH₂)_(o)(CHR⁶¹)_(s)CO— can be combined with linker L15 or L16and the resulting combination with

[0215] —(CH₂)_(m)(CHR⁶¹)_(s)X—, —(CH₂)_(o)(CHR⁶¹)_(s)X—,—(CH₂)_(p)(CHR⁶¹)_(s)X—, —(CH₂)_(q)(CHR⁶¹)_(s)X—; or —(CHR⁶¹)_(s)X—;

[0216] —(CH₂)_(p)(CHR⁶¹)_(s)CO— can be combined with linker L15 or L16and the resulting combination with

[0217] —(CH₂)_(m)(CHR⁶¹)_(s)X—, —(CH₂)_(o)(CHR⁶¹)_(s)X—,—(CH₂)_(o)(CHR⁶¹)_(s)X—, —(CH₂)_(q)(CHR⁶¹)_(s)X—; or —(CHR⁶¹)_(s)X—;

[0218] —(CH₂)_(q)(CHR⁶¹)_(s)CO— can be combined with linker L15 or L16and the resulting combination with

[0219] —(CH₂)_(m)(CHR⁶¹)_(s)X—, —(CH₂)_(o)(CHR⁶¹)_(s)X—,—(CH₂)_(p)(CHR⁶¹)_(s)X—, —(CH₂)_(q)(CHR⁶¹)_(s)X—; or —(CHR⁶¹)_(s)X—;

[0220] —(CH₂)_(r)(CHR⁶¹)_(s)CO— can be combined with linker L15 or L16and the resulting combination with

[0221] —(CH₂)_(m)(CHR⁶¹)_(s)X—, —(CH₂)_(o)(CHR⁶¹)_(s)X—,—(CH₂)_(p)(CHR⁶¹)_(s)X—, —(CH₂)_(q)(CHR⁶¹)_(s)X—; or —(CHR⁶¹)_(s)X—;

[0222] —(CHR⁶¹)_(s)CO— can be combined with linker L15 or L16 and theresulting combination with

[0223] —(CH₂)_(m)(CHR⁶¹)_(s)X—; —(CH₂)_(o)(CHR⁶¹)_(s)X—;—(CH₂)_(p)(CHR⁶¹)_(s)X—; —(CH₂)_(q)(CHR⁶¹)_(s)X—; or —(CHR⁶¹)_(s)X—;

[0224] Z, Z¹ and Z² independently are chains of n α-amino acid residues,n being an integer from 8 to 16, the positions of said amino acidresidues in said chains being counted starting from the N-terminal aminoacid, whereby these amino acid residues are, depending on their positionin the chains, Gly, or Pro, or of formula -A-CO—, or of formula —B—CO—,or of one of the types

[0225] C: —NR²⁰CH(R⁷²)CO—;

[0226] D: —NR²⁰CH(R⁷³)CO—;

[0227] E: —NR²⁰CH(R⁷⁴)CO—;

[0228] F: —NR²⁰CH(R⁸⁴)CO—; and

[0229] H: —NR²⁰ 13 (CH(CO—)—(CH₂)₄₋₇—(CH(CO—)—NR²⁰—;—NR²⁰—CH(CO—)—(CH₂)_(p)SS(CH₂)_(p)—(CH(CO—)—NR²⁰—;—NR²⁰—CH(CO—)—(CH₂)_(p)NR²⁰CO(CH₂)_(p)CH(CO—)—NR²⁰—; and—NR²⁰—(CH(CO—)—(—(CH₂)_(p)NR²⁰CONR²⁰(CH₂)_(p)—(CH(CO—)—NR²⁰—;

[0230] R⁷¹ is H; lower alkyl; lower alkenyl; —(CH₂)_(p)(CHR⁶¹)_(s)OR⁷⁵;—(CH₂)_(p)(CHR⁶¹)_(s)SR⁷⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(o)(CHR⁶¹)_(s)COOR⁷⁵; —(CH₂)_(p)CONR⁵⁸R⁵⁹; —(CH₂)_(p)PO(OR⁶²)₂;—(CH₂)_(p)SO₂R⁶²; or —(CH₂)_(o)—C₆R⁶⁷R^(ε)R^(Ε)R⁷⁰R⁷⁶;

[0231] R⁷² is H; lower alkyl; lower alkenyl; —(CH₂)_(p)(CHR⁶¹)_(s)OR⁸⁵;or —(CH₂)_(p)(CHR⁶¹)_(s)SR⁸⁵;

[0232] R⁷³ is —(CH₂)_(o)R⁷⁷; —(CH₂)_(r)O(CH₂)_(o)R⁷⁷;—(CH₂)_(r)S(CH₂)_(o)R⁷⁷; or —(CH₂)_(r)NR²⁰(CH₂)_(o)R⁷⁷;

[0233] R⁷⁴ is —(CH₂)_(p)NR⁷⁸R⁷⁹; —(CH₂)_(p)NR⁷⁷R⁸⁰;—(CH₂)_(p)C(═NR⁸⁰)NR⁷⁸R⁷⁹; —(CH₂)_(p)C(═NOR⁵⁰)NR⁷⁸R⁷⁹;—(CH₂)_(p)C(NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹; —(CH₂)_(p)NR⁸⁰C(═NR⁸⁰)NR⁷⁸R⁷⁹;—(CH₂)_(p)N═C(NR⁷⁸R⁸⁰)NR⁷⁹R⁸⁰; —(CH₂)_(p)C₆H₄NR⁷⁸R⁷⁹;—(CH₂)_(p)C₆H₄NR⁷⁷R⁸⁰; —(CH₂)_(p)C₆H₄C(═NR⁸⁰)NR⁷⁸R⁷⁹;—(CH₂)_(p)C₆H₄C(═NOR⁵⁰)NR⁷⁸R⁷⁹; —(CH₂)_(p)C₆H₄C(═NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹;—(CH₂)_(p)C₆H₄NR⁸⁰C(═NR⁸⁰)NR⁷⁸R⁷⁹; —(CH₂)_(p)C₆H₄N═C(NR⁷⁸R⁸⁰)NR⁷⁹NR⁸⁰;—(CH₂)_(r)O(CH₂)_(m) NR⁷⁸R⁷⁹; —(CH₂)_(r)O(CH₂)_(m)NR⁷⁷R⁸⁰;—(CH₂)_(r)O(CH₂)_(p)C(—NR⁸⁰)NR⁷⁸R⁷⁹;—(CH₂)_(r)O(CH₂)_(p)C(═NOR⁵⁰)NR⁷⁸R⁷⁹;—(CH₂)_(r)O(CH₂)_(p)C(—NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹;—(CH₂)_(r)O(CH₂)_(m)NR⁸⁰C(═NR⁸⁰)NR⁷⁸R⁷⁹;—(CH₂)_(r)O(CH₂)_(m)N═C(NR⁷⁸R⁸⁰)NR⁷⁹R⁸⁰; —(CH₂)_(r)O(CH₂)_(p)CNR⁷⁸R⁷⁹;—(CH₂)_(r)O(CH₂)_(p)C₆H₄C(═NR⁸⁰)NR⁷⁸R⁷⁹;—(CH₂)_(r)O(CH₂)_(p)C₆H₄C(═NOR⁵⁰)NR₇₈R⁷⁹;—(CH₂)_(r)O(CH₂)_(p)C₆H₄C(═NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹;—(CH₂)_(r)O(CH₂)_(p)C₆H₄NR⁸⁰C(═NR⁸⁰)NR⁷⁸R⁷⁹;—(CH₂)_(r)S(CH₂)_(m)NR⁷⁸R⁷⁹; —(CH₂)_(r)S(CH₂)_(m)NR⁷⁷R⁸⁰;—(CH₂)_(r)S(CH₂)_(p)C(═NR⁸⁰)NR⁷⁸R⁷⁹;—(CH₂)_(r)S(CH₂)_(p)C(═NOR⁵⁰)NR⁷⁸R⁷⁹;—(CH₂)_(r)S(CH₂)_(p)C(—NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹;—(CH₂)_(r)S(CH₂)_(m)NR⁸⁰C(═NR⁸⁰)NR⁷⁸R⁷⁹;—(CH₂)_(r)S(CH₂)_(m)N═C(NR⁷⁸R⁸⁰)NR⁷⁹R⁸⁰;—(CH₂)_(r)S(CH₂)_(p)C₆H₄CNR⁷⁸R⁷⁹;—(CH₂)_(r)S(CH₂)_(p)C₆H₄C(—NR⁸⁰)NR⁷⁸R⁷⁹;—(CH₂)_(r)S(CH₂)_(p)C₆H₄C(═NOR⁵⁰)NR⁷⁸R⁷⁹;—(CH₂)_(r)S(CH₂)_(p)C₆H₄C(═NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹;—(CH₂)_(r)S(CH₂)_(p)C₆H₄NR⁸⁰C(═NR⁸⁰)NR⁷⁸R⁷⁹; —(CH₂)_(p)NR⁸⁰COR⁶⁴;—(CH₂)_(p)NR⁸⁰COR⁷⁷; —(CH₂)_(p)NR⁸⁰CONR⁷⁸R⁷⁹; or—(CH₂)_(p)C₆H₄NR⁸⁰CONR⁷⁸R⁷⁹;

[0234] R⁷⁵ is lower alkyl; lower alkenyl; or aryl-lower allyl;

[0235] R³³ and R⁷⁸ taken together can form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;

[0236] R⁷⁵ and R⁸² taken together can form —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;

[0237] R⁷⁶ is H; lower alkyl; lower alkenyl; aryl-lower alkyl;—(CH₂)_(o)OR⁷²; —(CH₂)_(o)SR⁷²; —(CH₂)_(o)NR³³R³⁴; —(CH₂)_(o)OCONR³³R⁷⁵;—(CH₂)_(o)NR²⁰CONR³³R⁸²; —(CH₂)_(o)COOR⁷⁵; —(CH₂)_(o)CONR⁵⁸R⁵⁹;—(CH₂)_(o)PO(OR⁶⁰)₂; —(CH₂)_(p)SO₂R⁶²; or —(CH₂)_(o)COR⁶⁴;

[0238] R⁷⁷ is —C₆R⁶⁷R⁶¹R⁶⁹R⁷⁰R⁷⁶; or a heteroaryl group of one of theformulae

[0239] R⁷⁸ is H; lower alkyl; aryl; or aryl-lower alkyl;

[0240] R⁷⁸ and R⁸² taken together can form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;—(CH₂)S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;

[0241] R⁷⁹ is H; lower alkyl; aryl; or aryl-lower alkyl; or

[0242] R⁷⁸ and R⁷⁹, taken together, can be —(CH₂)₂₋₇—; —(CH₂)₂O(CH₂)₂—;or —(CH₂)₂NR⁵⁷(CH₂)₂—;

[0243] R⁸⁰ is H; or lower alkyl;

[0244] R⁸¹ is H; lower alkyl; or aryl-lower alkyl;

[0245] R⁸² is H; lower alkyl; aryl; heteroaryl; or aryl-lower alkyl;

[0246] R³³ and R⁸² taken together can form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;

[0247] R⁸³ is H; lower allyl; aryl; or —NR⁷⁸R⁷⁹;

[0248] R⁸⁴ is —(CH₂)_(m)(CHR⁶¹)_(s)OH; —(CH₂)_(p)CONR⁷⁸R⁷⁹;—(CH₂)_(p)NR⁸⁰CONR⁷⁸R⁷⁹; —(CH₂)_(p)C₆H₄CONR⁷⁸R⁷⁹; or—(CH₂)_(p)C₆H₄NR⁸⁰CONR⁷⁸R⁷⁹;

[0249] R⁸⁵ is lower alkyl; or lower alkenyl;

[0250] with the proviso that in said chain(s) of n α-amino acid residuesZ, Z¹ and Z²

[0251] if n is 8, the amino acid residues in positions 1 to 8 are:

[0252] P1: of type C or of type D or of type E or of type F, or theresidue is Pro;

[0253] P2: of type E or of type D or of type F;

[0254] P3: of type E or of type C, or the residue is Pro;

[0255] P4: of type E or of formula -A-CO—;

[0256] P5: of type E or of formula —B—CO—, or the residue is Gly;

[0257] P6: of type D, or the residue is Pro;

[0258] P7: of type or of type C or of type D; and

[0259] P8: of type C or of type D or of type E or of type F, or theresidue is Pro; or

[0260] P2 and P7, taken together, can form a group of type H; and at P4and P5 also D-isomers being possible;

[0261] if n is 9, the amino acid residues in positions 1 to 9 are:

[0262] P1: of type C or of type D or of type E or of type F, or theresidue is Pro;

[0263] P2: of type E or of type D or of type F;

[0264] P3: of type C or of type D or of type E, or the residue is Pro;

[0265] P4: of type E or of type D, or the residue is Pro;

[0266] P5: of type E, or the residue is Gly or Pro;

[0267] P6: of type D or of type E, or the residue is Gly or Pro;

[0268] P7: of type E or of type D or of type C, or the residue is Pro;

[0269] P8: of type E or of type D; and

[0270] P9: of type C or of type D or of type E or of type F, or theresidue is Pro; or

[0271] P2 and P8, taken together, can form a group of type H; and at P4,P5 and P6 also D-isomers being possible;

[0272] if n is 10, the amino acid residues in positions 1 to 10 are:

[0273] P1: of type C or of type D or of type E or of type F, or theresidue is Pro;

[0274] P2: of type E or of type D, or the residue is Pro;

[0275] P3: of type C or of type E;

[0276] P4: of type E or of type D or of type F, or the residue is Pro;

[0277] P5: of type E or of type F or of formula -A-CO—, or the residueis Gly;

[0278] P6: of type E or of formula —B—CO—, or the residue is Gly;

[0279] P7: of type D or of type E, or the residue is Gly or Pro;

[0280] P8: of type D or of type E;

[0281] P9: of type E or of type D or of type C, or the residue is Pro;and

[0282] P10: of type C or of type D or of type E or of type F; or

[0283] P3 and P8, taken together, can form a group of type H; and at P5and P6 also D-isomers being possible;

[0284] if n is 11, the amino acid residues in positions 1 to 11 are:

[0285] P1: of type C or of type D or of type E or of type F, or theresidue is Pro;

[0286] P2: of type E or of type C or of type D;

[0287] P3: of type D or of type E, or the residue is Pro;

[0288] P4: of type E or of type C or of type F;

[0289] P5: of type E or of type F, or the residue is Gly or Pro;

[0290] P6: of type E or of type F, or the residue is Gly or Pro;

[0291] P7: of type E or of type F, or the residue is Gly or Pro;

[0292] P8: of type D or of type E or of type F;

[0293] P9: of type D or of type E, or the residue is Pro;

[0294] P10: of type E or of type C or of type D; and

[0295] P11: of type C or of type D or of type E or of type F, or theresidue is Pro; or

[0296] P4 and P8 and/or P2 and P10, taken together, can form a group oftype H; and at P5, P6 and P7 also D-isomers being possible;

[0297] if n is 12, the amino acid residues in positions 1 to 12 are:

[0298] P1: of type C or of type D or of type E or of type F, or theresidue is Pro;

[0299] P2: of type E or of type D;

[0300] P3: of type C or of type D, or the residue is Pro;

[0301] P4: of type E or of type F or of type D;

[0302] P5: of type E or of type D or of type C, or the residue is Gly orPro;

[0303] P6: of type E or of type F or of formula -A-CO—, or the residueis Gly;

[0304] P7: of type E or of type F or of formula —B—CO—;

[0305] P8: of type D or of type C, or the residue is Pro;

[0306] P9: of type E or of type D or of type F;

[0307] P10: of type D or of type C, or the residue is Pro;

[0308] P11: of type E or of type D; and

[0309] P12: of type C or of type D or of type E or of type F, or theresidue is Pro; or

[0310] P4 and P9 and/or P2 and P11, taken together, can form a group oftype H; and

[0311] at P6 and P7 also D-isomers being possible;

[0312] if n is 13, the amino acid residues in positions 1 to 13 are:

[0313] P1: of type C or of type D or of type E or of type F, or theresidue is Pro;

[0314] P2: of type E or of typeF or of type D;

[0315] P3: of type C or of type D or of type E, or the residue is Pro;

[0316] P4: of type E of type C or of type F;

[0317] P5: of type E or of type D, or the residue is Gly or Pro;

[0318] P6: of type B or of type F, or the residue is Gly or Pro;

[0319] P7: of type E or of type F, or the residue is Pro;

[0320] P8: of type D or of type E or of type F, or the residue is Pro;

[0321] P9: of type D or of type E, or the residue is Pro;

[0322] P10: of type E or of type C or of type F;

[0323] P11: of type C or of type E, or the residue is Pro;

[0324] P12: of type E or of type D or of type C; and

[0325] P13: of type C or of type D or of type E or of type F, or theresidue is Pro; or

[0326] P4 and P10 and/or P2 and P12, taken together, can form a group oftype H;

[0327] and at P6, P7 and P8 also D-isomers being possible;

[0328] if n is 14, the amino acid residues in positions 1 to 14 are:

[0329] P1: of type C or of type D or of type E or of type F, or theresidue is Pro;

[0330] P2: of type E or of type C or of type D, or the residue is Pro;

[0331] P3: of type C or of type D or of type E;

[0332] P4: of type D or of type C or of type E, or the residue is Pro;

[0333] P5: of type E or of type D;

[0334] P6: of type E or of type F, or the residue is Gly or Pro;

[0335] P7: of type E or of type F or of formula -A-CO—, or the residueis Gly;

[0336] P8: of type E or of type F or of formula —B—CO—, or the residueis Gly;

[0337] P9: of type D or of type E, or the residue is Pro;

[0338] P10: of type C or of type D or of type E;

[0339] P11: of type E or of type D or of type F, or the residue is Pro;

[0340] P12: of type D or of type E;

[0341] P13: of type E or of type C or of type D, or the residue is Pro;and

[0342] P14: of type C or of type D or of type E or of type F, or theresidue is Pro; or

[0343] P5 and P10 and/or P3 and P12, taken together, can form a group oftype H;

[0344] and at P7 and P8 also D-isomers being possible;

[0345] if n is 15, the amino acid residues in positions 1 to 15 are:

[0346] P1: of type C or of type D or of type E or of type F, or theresidue is Pro;

[0347] P2: of type E or of type F or of type D;

[0348] P3: of type C or of type D or of type E, or the residue is Pro;

[0349] P4: of type E or of type D or of type F;

[0350] P5: of type C or of type D or of type E, or the residue is Pro;

[0351] P6: of type E or of type D or of type F;

[0352] P7: of type C or of type E, or the residue is Pro;

[0353] P8: of type E or of type F, or the residue is Gly or Pro;

[0354] P9: of type E or of type F, or the residue is Gly or Pro;

[0355] P10: of type E or of type D;

[0356] P11: of type C or of type D or of type E, or the residue is Pro;

[0357] P12: of type E or of type C or of type F;

[0358] P13: of type D or of type E, or the residue is Pro;

[0359] P14: of type E or of type C or of type D; and

[0360] P15: of type C or of type D or of type E or of type F, or theresidue is Pro; or

[0361] P6 and P10 and/or P4 and P12 and/or P2 and P14, taken together,can form a group of type H; and at P7, P8 and P9 also D-isomers beingpossible; and

[0362] if n is 16, the amino acid residues in positions 1 to 16 are:

[0363] P1: of type D, or of type E or of type C or of type F, or theresidue is Pro;

[0364] P2: of type E or of type F or of type D;

[0365] P3: of type C or of type D or of type E, or the residue is Pro;

[0366] P4: of type E or of type D or of type F;

[0367] P5: of type D or of type C or of type E, or the residue is Pro;

[0368] P6: of type E or of type D;

[0369] P7: of type E or of type F, or the residue is Gly or Pro;

[0370] P8: of type E or of type F or of formula -A-CO—, or the residueis Gly;

[0371] P9: of type E or of formula —B—CO—, or the residue is Gly;

[0372] P10: of type D or of type E, or the residue is Pro;

[0373] P11: of type E or of type C or of type D;

[0374] P12: of type D or of type C or of type E, or the residue is Pro;

[0375] P13; of type E or of type C or of type F;

[0376] P14: of type C or of type D or of type E, or the residue is Pro;

[0377] P15: of type E or of type C or of type D; and

[0378] P16: of type C or of type D or of type E or of type F, or theresidue is Pro; or

[0379] P6 and P11 and/or P4 and P13 and/or P2 and P15, taken together,can form a group of type H; and at P8 and P9 also D-isomers beingpossible;

[0380] and pharmaceutically acceptable salts thereof.

[0381] In accordance with the present invention these β-hairpinpeptidomimetics can be prepared by a process which comprises

[0382] (a) coupling an appropriately functionalized solid support withan appropriately N-protected derivative of that amino acid which in thedesired end-product is in position n/2, n/2+1 or n/2−1 if n is an evennumber and, respectively, in position n/2+½ or n/2−½ if n is an oddnumber, any functional group which may be present in said N-protectedamino acid derivative being likewise appropriately protected;

[0383] (b) removing the N-protecting group from the product thusobtained;

[0384] (c) coupling the product thus obtained with an appropriatelyN-protected derivative of that amino acid which in the desiredend-product is one position nearer the N-termninal amino acid residue,any functional group which may be present in said N-protected amino acidderivative being likewise appropriately protected;

[0385] (d) removing the N-protecting group from the product thusobtained;

[0386] (e) repeating, if necessary, steps (c) and (d) until theN-terminal amino acid residue has been introduced;

[0387] (f) coupling the product thus obtained to a compound of thegeneral formula

[0388] wherein

[0389] is as defined above and X is an N-protecting group or, if

[0390] is to be group (a1) or (a2), above, alternatively

[0391] (fa) coupling the product obtained in step (d) or (e) with anappropriately N-protected derivative of an amino acid of the generalformula

HOOC—B—H  III

or

HOOC-A-H  IV

[0392] wherein B and A are as defined above, any functional group whichmay be present in said N-protected amino acid derivative being likewiseappropriately protected;

[0393] (fb) removing the N-protecting group from the product thusobtained; and

[0394] (fc) coupling the product thus obtained with an appropriatelyN-protected derivative of an amino acid of the above general formula IVand, respectively, m, any functional group which may be present in saidN-protected amino acid derivative being likewise appropriatelyprotected;

[0395] (g) removing the N-protecting group from the product obtained instep (f) or (fc);

[0396] (h) coupling the product thus obtained to an appropriatelyN-protected derivative of that amino acid which in the desiredend-product is in position n, any functional group which may be presentin said N-protected amino acid derivative being likewise appropriatelyprotected;

[0397] (i) removing the N-protecting group from the product thusobtained;

[0398] (j) coupling the product thus obtained to an appropriatelyN-protected derivative of that amino acid which in the desiredend-product is one position farther away from position n, any functionalgroup which may be present in said N-protected amino acid derivativebeing likewise appropriately protected;

[0399] (k) removing the N-protecting group from the product thusobtained;

[0400] (l) repeating, if necessary, steps (1) and (I) until all aminoacid residues have been introduced;

[0401] (m) if desired, selectively deprotecting one or several protectedfunctional group(s) present in the molecule and appropriatelysubstituting the reactive group(s) thus liberated;

[0402] (o) detaching the product thus obtained from the solid support;

[0403] (p) cyclizing the product cleaved from the solid support;

[0404] (q) if, desired

[0405] (qa) forming one or several interstrand linkage(s) betweenside-chains of appropriate amino acid residues at opposite positions ofthe Fstand region; and/or

[0406] (qb) connecting two building blocks of the type of formula Ia viaa bridge -G1-L-G2-;

[0407] (r) removing any protecting groups present on functional groupsof any members of the chain of amino acid residues and, if desired, anyprotecting group(s) which may in addition be present in the molecule;and

[0408] (s) if desired, converting the product thus obtained into apharmaceutically acceptable salt or converting a pharmaceuticallyacceptable, or unacceptable, salt thus obtained into the correspondingfree compound of formula I or into a different, pharmaceuticallyacceptable, salt.

[0409] The peptidomimetics of the present invention can also beenantiorners of the compounds of formulae Ia and Ib. These enantiomerscan be prepared by a modification of the above process in whichenantiomers of all chiral starting materials are used.

[0410] As used in this description, the term “alkyl”, taken alone or incombinations, designates saturated, straight-chain or branchedhydrocarbon radicals having up to 24, preferably up to 12, carbon atoms.Similarly, the term “alkenyl” designates straight chain or branchedhydrocarbon radicals having up to 24, preferably up to 12, carbon atomsand containing at least one or, depending on the chain length, up tofour olefinic double bonds. The term “lower” designates radicals andcompounds having up to 6 carbon atoms. Thus, for example, the term“lower alkyl” designates saturated, straight-hain or branchedhydrocarbon radicals having up to 6 carbon atoms, such as methyl, ethyl,n-propyl, isopropyl, n-butyl, sec.-butyl, isobutyl, tert.-butyl and thelike. The term “aryl” designates aromatic carbocyclic hydrocarbonradicals containing one or two six-membered rings, such as phenyl ornaphthyl, which may be substituted by up to three substituents such asBr, Cl, F, CF₃, NO₂, lower alkyl or lower alkenyl. The term “heteroaryl”designates aromatic heterocyclic radicals containing one or two five-and/or six-membered rings, at least one of them containing up to threeheteroatoms selected from the group consisting of O, S and N and saidring(s) being optionally substituted; representative examples of suchoptionally substituted heteroaryl radicals are indicated hereinabove inconnection with the definition of R⁵⁷.

[0411] The structural element -A-CO— designates amino acid buildingblocks which in combination with the structural element —B—CO— formtemplates (a1) and (a2). Templates (a) through (p) constitute buildingblocks which have an N-terminus and a C-terminus oriented in space insuch a way that the distance between those two groups may lie between4.0-5.5A. A peptide chain Z, Z¹ or Z² is linked to the C-terminus andthe N-terminus of the templates (a) through (p) via the corresponding N-and C-termini so that the template and the chain form a cyclic structuresuch as that depicted in formula Ia. In a case as here where thedistance between the N- and C-termini of the template lies between4.0-5.5A the template will induce the H-bond network necessary for theformation of a β-hairpin conformation in the peptide chain Z, Z¹ or Z².Thus template and peptide chain form a β-hairpin mimetic. The β-hairpinmimetics can also be coupled through groups G1 and G2 and a linker unitL to form the dimeric constructs of formula Ib.

[0412] The β-hairpin conformation is highly relevant for the antibioticand anticancer activities of the β-hairpin mimetics of the presentinvention. The β-hairpin stabilizing conformational properties of thetemplates (a) through (p) play a key role not only for antibiotic andanticancer activity but also for the synthesis process definedhereinabove, as incorporation of the templates near the middle of thelinear protected peptide precursors enhance significantly cyclizationyields.

[0413] Building blocks A1-A69 belong to a class of amino acids whereinthe N-terminus is a secondary amine forming part of a ring. Among thegenetically encoded amino acids only proline falls into this class. Theconfiguration of building block A1 through A69 is (D), and they arecombined with a building block —B—CO— of (L)-configuration. Preferredcombinations for templates (a1) are-^(D)A1-CO-^(L)B-CO— to^(D)A69-CO-^(L)B-CO—. Thus, for example, ^(D)Pro-^(L)Pro constitutes theprototype of templates (a1). Less preferred, but possible arecombinations where templates (a2) are -^(L)A1-CO-^(D)B-CO— to^(L)A69-CO-^(D)BCO—. Thus, for example, ^(L)Pro-^(D)Pro constitutes aless preferred prototype of template (a2).

[0414] It will be appreciated that building blocks -A1-CO— to -A69-CO—in which A has (D)-configuration, are carrying a group R¹ at thec-position to the N-terminus. The preferred values for R¹ are H andlower alkyl with the most preferred values for R¹ being H and methyl. Itwill be recognized by those skilled in the art, that A1-A69 are shown in(D)-configuration which, for R¹ being H and methyl, corresponds to the(R)-configuration. Depending on the priority of other values for R¹according to the Cahn, Ingold and Prelog-rules, this configuration mayalso have to be expressed as (S).

[0415] In addition to R¹ building blocks -A¹-CO— to -A69-CO— can carryan additional substituent designated as R² to R¹⁷. This additionalsubstituent can be H, and if it is other than H, it is preferably asmall to medium-sized aliphatic or aromatic group. Examples of preferredvalues for R² to R¹ are:

[0416] R²: H; lower alkyl; lower alkenyl; (CH₂)_(m)OR⁵⁵ (where R⁵⁵:lower alkyl; or lower alkenyl); —(CH₂)_(m)SR⁵⁶ (where R⁵⁶: lower alkyl;or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: lower alkyl; or loweralkenyl; R³⁴: H; or lower alkyl; R³³ and R³⁴ taken together form:—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;R⁵⁷: H; or lower alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lowerallyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken togetherform: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);—(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);—(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹:H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or loweralkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower ailcyl; or lower alkenyl);or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; loweralkenyl; or lower alkoxy).

[0417] R³: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:lower alkyl; or lower alkenyl); —(CH₂)_(m)SR⁵⁶ (where R⁵⁶: lower alkyl;or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: lower alkyl; or loweralkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; orlower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ takentogether form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);—(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);—(CH₂)_(o)CONW⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹:H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—, where R⁵⁷: H;or lower alkyl); —(CH₂)_(o)(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or loweralkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl);or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; loweralkenyl; or lower alkoxy).

[0418] R⁴: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:lower alkyl; or lower alkenyl); —(CH₂)_(m)S⁵⁶ (where R⁵⁶: lower alkyl;or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: lower alkyl; or loweralkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; orlower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ takentogether form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(m)NR²⁰CONR⁸²(where R²⁰: H; or lower lower alkyl; R³³: H; or lower alkyl; or loweralkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸² taken together form:—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H; orlower alkyl; R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷(where R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (whereR⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl; or R⁵⁸and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);—(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or—(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl;or lower alkoxy).

[0419] R⁵: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵: loweralkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower alkyl; orlower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower alkyl; or loweralkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; orlower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ takentogether form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; R⁵⁷: where H; or lower alkyl); —(CH₂)OCNR²⁰CONR³³R⁸²(where R²⁰: H; or lower lower alkyl; R³³: H; or lower alkyl; or loweralkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸² taken together form:—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H; orlower alkyl; R⁶: alkyl; alkenyl; aryl; and aryl-lower alkyl;heteroaryl-lower alkyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; orlower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or loweralkenyl; and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: loweralkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; orlower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; loweralkyl; lower alkenyl; or lower alkoxy).

[0420] R⁶: H; lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower alkyl;or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower alkyl; or loweralkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; orlower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ takentogether form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R₂₀)COR⁶⁴(where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);—(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);—(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹:H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or loweralkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl);or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; loweralkenyl; or lower alkoxy).

[0421] R⁷: lower alkyl; lower alkenyl; —(CH₂)_(q)OR⁵⁵ (where R⁵⁵: loweralkyl; or lower alkenyl); —(CH₂)_(q)SR⁵⁶ (where R⁵⁶: lower alkl; orlower alkenyl); —(CH₂)_(q)NR³³R³⁴ (where R³³: lower alkyl; or loweralkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(q)OCONR³³R⁷⁵ (where R³³: H; orlower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ takentogether form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(q)NR₂₀CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(q)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);—(CH₂)_(r)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);—(CH₂)_(q)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹:H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower alkyl); —(CH₂)_(r)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or loweralkenyl); —(CH₂)_(r)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl);or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; loweralkenyl;or lower alkoxy).

[0422] R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵(where R⁵⁵: lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶:lower alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: loweralkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ takentogether form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵(where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; orR³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);—(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);—(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹:H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂₎ ₂—; where R⁵⁷: H;or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or loweralkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl);or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; loweralkenyl; or lower alkoxy).

[0423] R⁹: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵: loweralkyl; or lower alkenyl); —(CH₂)_(o)SR⁵, (where R⁵⁶: lower alkyl; orlower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower alkyl; or loweralkenyl; R³⁴: H; or lower allyl; or R³³ and R³⁴ taken together form:—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; orlower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ takentogether form: —(CH₂)₂₋₆; —(CH₂)₂O(CH₂)₂—, —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower allyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);—(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);—(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹:H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or loweralkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl);or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; loweralkenyl; or lower alkoxy).

[0424] R¹⁰: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵: loweralkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower alkyl; orlower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower alkyl; or loweralkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; orlower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ takentogether form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower allyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);—(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);—(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹:H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—, or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower allyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or loweralkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl);or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; loweralkenyl; or lower alkoxy).

[0425] R¹¹: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:lower alkyl; or lower alkenyl); —(CH₂)_(m)SR⁵⁶ (where R⁵⁶: lower alkyl;or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: lower alkyl; or loweralkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; orlower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ takentogether form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH2)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; orlower alkenyl); —(CH₂)_(o)COOR⁵⁸ (where R⁵⁷: lower alkyl; or loweralkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁷: lower alkyl; or lower alkenyl;and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or loweralkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl);or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; loweralkenyl; or lower alkoxy).

[0426] R¹²: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:lower alkyl; or lower alkenyl); —(CH₂)_(m)SR⁵⁶ (where R⁵⁶: lower alkyl;or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: lower alkyl; or loweralkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; orlower alkyl; or lower alkenyl; R⁷⁵: lower allyl; or R³³ and R⁷⁸takentogether form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(m)CNR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);—(CH₂)_(r)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);—(CH₂)_(r)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹:H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower alkyl); —(CH₂)_(r)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or loweralkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl);or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; loweralkenyl; or lower alkoxy).

[0427] R¹³: lower alkyl; lower alkenyl; —(CH₂)_(q)OR⁵⁵ (where R⁵⁵: loweralkyl; or lower alkenyl); —(CH₂)_(q)SR⁵⁶ (where R⁵⁶: lower alkyl; orlower alkenyl); —(CH₂)_(q)NR³³R³⁴ (where R³³: lower alkyl; or loweralkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(q)OCONR³³R⁷⁵ (where R³³: H; orlower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ takentogether form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(q)NR²⁰CONR³W⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(q)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);—(CH₂)_(r)COO⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);—(CH₂)_(q)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹:H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower alkyl); —(CH₂)_(r)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or loweralkenyl); —(CH₂)_(r)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl);or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; loweralkenyl; or lower alkoxy).

[0428] R¹⁴: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:lower alkyl; or lower alkenyl); —(CH₂)_(m)SR⁵⁶ (where R⁵⁶: lower alkyl;or lower alkenyl); —(CH₂)_(m)>R³³R³⁴ (where R³³: lower alkyl; or loweralkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; orlower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ takentogether form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(r)CNR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴(where: R²⁰: H; lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);—(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);—(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; andR⁵⁸R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:—(CH₂)₂₋₆; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: loweralkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; orlower alkenyl); —(CH₂)_(q)C⁶H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl;lower alkenyl; or lower alkoxy).

[0429] R¹⁵: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵: loweralkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower alkyl; orlower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower alkyl; or loweraLkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; orlower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ takentogether form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);particularly favoured are NR²⁰COlower alkyl (R²⁰═H; or lower alkyl);—(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);—(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl; and R⁵⁹:H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or loweralkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl);or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; loweralkenyl; or lower alkoxy).

[0430] R¹⁶: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵: loweralkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower alkyl; orlower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower alkyl; or loweralkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; orlower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ takentogether form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);—(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);—(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹:H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or loweralkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl);or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; loweralkenyl; or lower alkoxy).

[0431] R¹⁷: lower alkyl; lower alkenyl; —(CH₂)_(q)OR⁵⁵ (where R⁵⁵: loweralkyl; or lower alkenyl); —(CH₂)_(q)SR⁵⁶ (where R⁵⁶: lower alkyl; orlower alkenyl); —(CH₂)_(q)NR³³R³⁴ (where R³³: lower alkyl; or loweralkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(q)OCONR³³R⁷⁵ (where R³³: H; orlower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ takentogether form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(q)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(q)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);—(CH₂)_(r)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);—(CH₂)_(q)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹:H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; orlower alkyl); —(CH₂)_(r)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or loweralkenyl); —(CH₂)_(r)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl);or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; loweralkenyl; or lower alkoxy).

[0432] Among the building blocks A1 to A69 the following are preferred:A5 with R² being H, A8, A22, A25, A38 with R² being H, A42, A47, andA50. Most preferred are building blocks of type A8′:

[0433] wherein R²⁰ is H or lower alkyl; and R⁶⁴ is alkyl; alkenyl; aryl;aryl-lower alkyl; or heteroaryl-lower alkyl; especially those whereinR⁶⁴ is n-hexyl (A8′-1); n-heptyl (A8′-2); 4-(pbenyl)benzyl (A8′-3);diphenylmethyl (A8′-4); 3-amino-propyl (A8′-5); 5-amino-pentyl (A8′-6);methyl (A8′-7); ethyl (A8′-8); isopropyl (A8′-9); isobutyl (A8′-10);n-propyl (A8′-11); cyclohexyl (A8′-12); cyclohexylmethyl (A8′-13);n-butyl (A8′-14); phenyl (A8′-15); benzyl (A8′-16); (3-indolyl)methyl(A8′-17); 2-(3-indolyl)ethyl (A8′-18); (4-phenyl)phenyl (A8′-19); andn-nonyl (A8′-20).

[0434] Building block A70 belongs to the class of open-chainedα-substituted α-amino acids, building blocks A71 and A72 to thecorresponding β-amino acid analogues and building blocks A73-A104 to thecyclic analogues of A70. Such amino acid derivatives have been shown toconstrain small peptides in well defined reverse turn or U-shapedconformations (C. M. Venkatachalam, Biopolymers, 1968, 6, 1425-1434; W.Kabsch, C Sander, Biopolymers 1983, 22, 2577). Such building blocks ortemplates are ideally suited for the stabilization of β-hairpinconformations in peptide loops (D. Obrecht, M. Altorfer, J. A. Robinson,“Novel Peptide Mimetic Building Blocks and Strategies for Efficient LeadFinding”, Adv. Med Chem. 1999, Vol.4, 1-68; P. Balaram, “Non-standardamino acids in peptide design and protein engineering”, Curr. Opin.Struct. Biol. 1992, 2, 845-851; M. Crisma, G. Valle, C. Toniolo, S.Prasad, R. B. Rao, P. Balaram, “β-turn conformations in crystalstructures of model peptides containing α,α-disubstituted amino acids”,Biopolymers 1995, 35, 1-9; V. J. Hruby, F. Al-Obeidi, W. Kazmierski,Biochem. J. 1990, 268, 249-262).

[0435] It has been shown that both enantiomers of building blocks-A70-CO— to A104-CO— in combination with a building block —B—CO— ofLconfiguration can efficiently stabilize and induce β-hairpinconformations (D. Obrecht, M. Altorfer, J. A. Robinson, “Novel PeptideMimetic Building Blocks and Strategies for Efficient Lead Finding”, Adv.Med Chem 1999, Vol.4, 1-68; D. Obrecht, C. Spiegler, P. Schorholm, K.Müller, H. Heimgartner, F. Stierli, Helv. Chin. Acta 1992, 75,1666-1696; D. Obrecht, U. Bohdal, J. Daly, C. Lehmann, P. Schönholzer,K. Müller, Tetrahedron 1995, 51, 10883-10900; D. Obrecht, C. Lehmann, C.Ruffieux, P. Schönholzer, K. Müller, Helv. Chim. Acta 1995, 78,1567-1587; D. Obrecht, U. Bohdal, C. BrogeT, D. Bur, C. Lehmann, RRuffieux, P. Schönholzer, C. Spiegler, Helv. Chim. Acta 1995, 78,563-580; D. Obrecht, H. Karajiannis, C. Lehmann, P. Schönholzer, C.

[0436] Spiegler, Helv. Chim. Acta 1995, 78, 703-714).

[0437] Thus, for the purposes of the present invention templates (a1)can also consist of -A70-CO— to A104-CO— where building block A70 toA104 is of either (D)- or (L)-configuration, in combination with abuilding block —B—CO— of (L)-configuration.

[0438] Preferred values for R²⁰ in A70 to A104 are H or lower alkyl withmethyl being most preferred. Preferred values for R¹⁸, R¹⁹ and R²¹—R²⁹in building blocks A70 to A104 are the following:

[0439] R¹⁸: lower alkyl.

[0440] R¹⁹: lower alkyl; lower alkenyl; —(CH₂)_(p)OR⁵⁵ (where R⁵⁵: loweralkyl; or lower alkenyl); —(CH₂)_(p)SR⁵⁶ (where R⁵⁶: lower alkyl; orlower alkenyl); —(CH₂)_(p)NR³³R³⁴ (where R³³: lower alkyl; or loweralkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(p)OCONR³³R⁷⁵ (where R³³: H; orlower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ takentogether form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(p)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(p)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);—(CH₂)_(p)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);—(CH₂)_(p)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹:H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower alkyl); —(CH₂)_(o)O(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or loweralkenyl); —(CH₂)_(p)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl);or —(CH₂)_(o)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; loweralkenyl; or lower alkoxy).

[0441] R²¹: H; lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower alkyl;or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower alkyl; or loweralkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; orlower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ takentogether form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);—(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);—(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl; and R⁵⁹:H; lower alkyl; or R⁵⁸ and R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or loweralkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl);or (CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl;or lower alkoxy).

[0442] R²¹: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵: loweralkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower alkyl; orlower alkenyl); —(CH₂)R³³R³⁴ (where R³³: lower alkyl; or lower alkenyl;R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form: —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; orlower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form:—(CH₂)₂₋₆—; —(CH₂)_(o)(CH₂)₂—; —(CH₂)₂S(CH₂)—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)R²⁰CONR³³R⁸² (where R²⁰: H; orlower lower alkyl; R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; orlower alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl;R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: loweralkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl,or lower alkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken togetherform: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂(where R⁶⁰: lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²:lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl;CF; lower alkyl; lower alkenyl; or lower alkoxy).

[0443] R²³: H; lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower alkyl;or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower alkyl; or loweralkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; orlower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ takentogether form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²¹)COR(where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);particularly favoured are NR²⁰CO lower alkyl (R²⁰═H; or lower alkyl);—(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);—(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl; and R⁵⁹:H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or loweralkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl);or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃, lower alkyl; loweralkenyl; or lower alkoxy);

[0444] R²⁴: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵: loweralkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower alkyl; orlower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower alkyl; or loweralkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; orlower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ takentogether form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);particularly favoured are NR²⁰CO lower alkyl (R²⁰═H ; or lower alkyl);—(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);—(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl; and R⁵⁹:H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or loweralkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl);or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; loweralkenyl; or lower alkoxy);

[0445] R²⁵: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:lower alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: loweralkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ takentogether form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(m)OCONR³³R⁷⁵(where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; orR³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower allyl; R⁶⁴: lower alkyl; or lower alkenyl);—(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);—(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower-alkenyl; and R⁵⁹:H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or loweralkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl);or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; loweralkenyl; or lower alkoxy).

[0446] R²⁶: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:lower alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: loweralkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ takentogether form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(m)OCONR³³R⁷⁵(where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; orR³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);—(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);—(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹:H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or loweralkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl);or —(CH₂)_(q)C₆H⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl;or lower alkoxy).

[0447] Alternatively. R²⁵ and R²⁶ taken together can be —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower alkyl).

[0448] R²⁷: H; lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower alkyl;or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower alkyl; or loweralkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; orlower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ takentogether form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);—(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);—(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl; and R⁵⁹:H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower allyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or loweralkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl);or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; loweralkenyl; or lower alkoxy).

[0449] R²⁸: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵: loweralkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower alkyl; orlower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower alkyl; or loweralkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; orlower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ takentogether form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴(where R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);—(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);—(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl; and R⁵⁹:H; lower allyl; or R⁵⁸ and R⁵⁹ taken together form —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or loweralkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl);or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; loweralkenyl; or lower alkoxy).

[0450] R²⁹: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵: loweralkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower alkyl; orlower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower alkyl; or loweralkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; orlower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ takentogether form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(o)N(R²⁰)_(o)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: loweralkyl; or lower alkenyl); particularly favored are NR²⁰COlower-alkyl(R²⁰═H; or lower alkyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; orlower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or loweralkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: loweralkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; orlower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; loweralkyl; lower alkenyl; or lower alkoxy).

[0451] For templates (b) to (p), such as (b1) and (c1), the preferredvalues for the various symbols are the following:

[0452] R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵(where R⁵⁵: lower alkyl; or lower alkenyl); —(CH₂)_(s)R⁵⁶ (where R⁵⁶:lower alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: loweralkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ takentogether form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵(where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; orR³³ and R⁷⁵ taken together form: —(CH₂)₂—; —(CH₂)₂O(CH₂)₂—;—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);—(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);—(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁷⁵: lower alkyl; or lower alkenyl; and R⁵⁹:H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or loweralkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl);or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; loweralkenyl; or lower alkoxy).

[0453] R²⁰: H; or lower alkyl.

[0454] R³⁰: H, methyl.

[0455] R³¹: H; lower alkyl; lower alkenyl; —(CH₂)_(p)OR⁵⁵ (where R⁵⁵:lower alkyl; or lower alkenyl); —(CH₂)_(p)R³³R³⁴ (where R³³: loweralkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ takentogether form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(p)OCONR³³R⁷⁵⁷(where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; orR³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(p)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(p)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);—(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);(—(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl; and R⁵⁹:H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or loweralkenyl); —(CH₂)OSO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or—(CH₂)_(r)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl;or lower alkoxy); most preferred is —H₂CONR⁵⁸R⁵⁹ (R⁵⁸: H; or loweralkyl; R⁵⁹: lower alkyl; or lower alkenyl).

[0456] R³²: H, methyl.

[0457] R³³: lower alkyl; lower alenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵: lowerakyl; or lower alkenyl); —(CH₂)_(m)NR³⁴R⁶³ (where R³⁴: lower alkyl; orlower alkenyl; R⁶³: H; or lower alkyl; or R³⁴ and R⁶³ taken togetherform: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(m)OCONR⁷⁵R⁸²(where R⁷⁵: lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; orR⁷⁵ and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(m)NR²⁰CONR⁷⁸R⁸² (where R²⁰: H; or lower lower alkyl; R⁷⁸: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R⁷⁸ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)_(o)NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl;or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or loweralkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower alkyl).

[0458] R³⁴: H; or lower alkyl.

[0459] R³⁵: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:lower alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: loweralkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ takentogether form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵(where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; orR³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);—(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);—(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹:H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; orlower alkyl).

[0460] R³⁶: lower alkyl; lower alkenyl; or aryl-lower alkyl.

[0461] R³⁷: H; lower alkyl; lower alkenyl; —(CH₂)_(p)OR⁵⁵ (where R⁵⁵:lower alkyl; or lower alkenyl); —(CH₂)_(p)NR³³R³⁴ (where R³³: loweralkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ takentogether form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower ak1); —(CH₂)_(p)OCONR³³R⁷⁵(where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; orR³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(p)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower alkyl; R³³: H; or loweralkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸² takentogether form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(p)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);—(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);—(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl; and R⁵⁹:H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or loweralkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alky; or lower alkenyl); or—(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl;or lower alkoxy).

[0462] R³⁸: H; lower alkyl; lower alkenyl; —(CH₂)_(p)OR⁵⁵ (where R⁵⁵:lower alkyl; or lower alkenyl); —(CH₂)_(p)NR³³R³⁴ (where R³³: loweralkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ takentogether form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(p)OCONR³³R⁷⁵(where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; orR³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(p)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(p)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);—(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);—(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl; and R⁵⁹:H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or loweralkenyl); —(CH₂)_(o)SO₂R⁸² (where R⁶²: lower alkyl; or lower alkenyl);or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; loweralkenyl; or lower alkoxy).

[0463] R³⁹: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:lower alkyl; or lower alkenyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H; orlower alkyl; R⁶⁴: lower allyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷(where R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (whereR⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸ andR⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—,or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl).

[0464] R⁴⁰: lower alkyl; lower alkenyl; or aryl-lower alkyl.

[0465] R⁴¹: H; lower alkyl; lower alkenyl; —(CH₂)_(p)OR⁵⁵ (where R⁵⁵:lower alkyl; or lower alkenyl); —(CH₂)_(p)NR³³R³⁴ (where R³³: loweralkyl; or lower alkenyl; R³⁴: H; or lower alyl; or R³³ and R³⁴ takentogether form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—, —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(p)OCONR³³R⁷⁵(where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; orR³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(p)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(p)N(R²⁰)COR(where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);—(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);—(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl or lower alkenyl; and R⁵⁹:H; lower alky; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alsyl; or loweralkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl);or —(CH₂)_(q)C₆C₄R⁸ (where R⁸¹: H; F; Cl; CF₃; lower alkyl; loweralkenyl; or lower alkoxy).

[0466] R⁴²: H; lower alkyl; lower alkenyl; —(CH₂)_(p)OR⁵⁵ (where R⁵⁵:lower alkyl; or lower alkenyl); —(CH₂)_(p)NR³³R³⁴ (where R³³: loweralkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ takentogether form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(p)OCONR³³R⁷⁵(where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; orR³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—, where R⁵⁷: H; or lower alkyl);—(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(p)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);—(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);—(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl; and R⁵⁹:H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or loweralkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl);or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; loweralkenyl; or lower alkoxy).

[0467] R⁴³: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:lower alkyl; or lower alkenyl); —(CH₂)_(m)SR⁵⁶ (where R⁵⁶: lower alkyl;or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: lower alkyl; or loweralkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; orlower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ takentogether form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)R²⁰CONR³³R⁸²(where R²⁰: H; or lower lower alkyl; R³³: H; or lower alkyl; or loweralkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸² taken together form:—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H; orlower alkyl; R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷(where R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (whereR⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸ andR⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—;or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R¹⁷: H; or lower alkyl);—(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);—(CH₂)_(o)SO₂R⁶² (where R⁶²: lower allyl; or lower alkenyl); or—(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl;or lower alkoxy).

[0468] R⁴⁴: lower alkyl; lower alkenyl; —(CH₂)_(p)OR⁵⁵ (where R⁵⁵: loweralkyl; or lower alkenyl); —(CH₂)_(p)SR⁵⁶ (where R⁵⁶: lower alkyl; orlower alkenyl); —(CH₂ N³³R³⁴ (where R³: lower alkyl; or lower alkenyl;R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form: —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower alkyl); —(CH₂)_(p)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; orlower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form:—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(p)NR²⁰CONR³³R⁸² (where R²⁰: H; orlower lower alkyl; R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; orlower alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—, —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower alkyl); —(CH₂)_(p)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl;R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(p)COOR⁵⁷ (where R⁵⁷: loweralkyl; or lower alkenyl); —(CH₂)_(p)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl;or lower alkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken togetherform: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); or —(CH₂)_(o)C₆H₄R⁸(where R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy).

[0469] R⁴⁵: H; lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower alkyl;or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower alkyl; or loweralkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(s)OCONR³³R⁷⁵ (where R³³: H; orlower alkyl; or lower alkenyl; R⁷⁵: lower allyl; or R³³ and R⁷⁵ takentogether form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower allyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—, —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);—(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);—(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹:H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower alkyl); or —(CH₂)_(s)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; loweralkyl; lower alkenyl; or lower alkoxy).

[0470] R⁴⁶: H; lower alkyl; lower alkenyl; —(CH₂)_(s)OR⁵⁵ (where R⁵⁵:lower alkyl; or lower alkenyl); —(CH₂)_(s)SR⁵⁶ (where R⁵⁶: lower alkyl;or lower alkenyl); —(CH₂)_(s)NR³³R³⁴ (where R³³: lower alkyl; or loweralkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)OCONR³³R⁷⁵ (where R³³: H; or loweralkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken togetherform: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(s)N(R²⁰)_(o)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lowerallyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; orlower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or loweralkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—, or —(CH₂)₂NR⁵⁷(CH₂)—;where R⁵⁷: H; or lower alkyl); or —(CH₂)_(s)C₆H₄R³ (where R⁸: H; F; Cl;CF₃; lower alkyl; lower alkenyl; or lower alkoxy).

[0471] R⁴⁷: H; or OR⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl).

[0472] R⁴⁸: H; or lower alkyl.

[0473] R⁴⁹: H; lower alkyl; —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; orlower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or loweralkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); or (CH₂)_(s)C₆H₄R⁸ (where R⁸: H; F; Cl;CF₃; lower alkyl; lower alkenyl; or lower alkoxy).

[0474] R⁵⁰: H; methyl.

[0475] R⁵¹: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:lower alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: loweralkyl; or lower alkenyl; R³: H; or lower alkyl; or R³³ and R³⁴ takentogether form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(m)OCONR³³R⁷⁵(where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; orR³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower allyl; or lower alkenyl; R⁸²: H; or lower allyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);—(CH₂)_(p)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);—(CH₂)_(p)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹:H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower alkyl); or —(CH₂)_(r)C₆H₄R⁸ (where R⁸⁵: H; F; Cl; CF₃; loweralkyl; lower alkenyl; or lower alkoxy).

[0476] R⁵²: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:lower alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: loweralkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ takentogether form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(m)OCONR³³R⁷⁵(where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; orR³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; R⁵⁷: H; or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);—(CH₂)_(p)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);—(CH₂)_(p)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹:H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower alkyl); or —(CH₂)_(r)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; loweralkyl; lower alkenyl; or lower alkoxy).

[0477] R⁵³: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:lower alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: loweralkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ takentogether form: —(CH₂)₂₋₆; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(m)OCONR³³R⁷⁵(where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; orR³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl; R⁶: lower alkyl; or lower alkenyl);—(CH₂)_(p)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);—(CH₂)_(p)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹:H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower alkyl); or —(CH₂)_(r)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; loweralkyl; lower alkenyl; or lower alkoxy).

[0478] R⁵⁴: lower alkyl; lower alkenyl; or aryl-lower alkyl.

[0479] Among the building blocks A70 to A104 the following arepreferred: A74 with R²² being H, A75, A76, A77 with R² being H, A78 andA79. The building block —B—CO— within template (a1) and (a2) designatesan L-amino acid residue. Preferred values for B are: —NR²⁰CH(R⁷¹)— andenantiomers of groups A5 with R² being H, A8, A22, A25, A38 with R²being H, A42, A47, and A50. Most preferred are Ala L-Alanine ArgL-Arginine Asn L-Asparagine Cys L-Cysteine Gln L-Glutamine Gly GlycineHis L-Histidine Ile L-Isoleucine Leu L-Leucine Lys L-Lysine MetL-Methionine Phe L-Phenylalanine Pro L-Proline Ser L-Serine ThrL-Threonine Trp L-Tryptophan Tyr L-Tyrosine Val L-Valine CitL-Citrulline Orn L-Ornithine tBuA L-t-Butylalanine Sar Sarcosine t-BuGL-tert.-Butylglycine 4AmPhe L-para-Aminophenylalanine 3AmPheL-meta-Aminophenylalanine 2AmPhe L-ortho-AminophenylalaninePhe(mC(NH₂)═NH) L-meta-Amidinophenylalanine Phe(pC(NH₂)═NH)L-para-Amidinophenylalanine Phe(mNHC (NH₂)═NH)L-meta-Guanidinophenylalanine Phe(pNHC (NH₂)═NH)L-para-Guanidinophenylalanine Phg L-Phenylglycine ChaL-Cyclohexylalanine C₄al L-3-Cyclobutylalanine C₅alL-3-Cyclopentylalanine Nle L-Norleucine 2-Nal L-2-Naphthylalanine 1-NalL-1-Naphthylalanine 4Cl-Phe L-4-Chlorophenylalanine 3Cl-PheL-3-Chlorophenylalanine 2Cl-Phe L-2-Chlorophenylalanine 3,4Cl₂-PheL-3,4-Dichlorophenylalanine 4F-Phe L-4-Fluorophenylalanine 3F-PheL-3-Fluorophenylalanine 2F-Phe L-2-Fluorophenylalanine TicL-1,2,3,4-Tetrahydroisoquinoline-3- carboxylic acid ThiL-β-2-Thienylalanine Tza L-2-Thiazolylalanine Mso L-Methionine sulfoxideAcLys L-N-Acetyllysine Dpr L-2,3-Diaminopropionic acid A₂BuL-2,4-Diaminobutyric acid Dbu (S)-2,3-Diaminobutyric acid Abuγ-Aminobutyric acid (GABA) Aha ε-Aminohexanoic acid Aibα-Aminoisobutyric acid Y(Bzl) L-O-Benzyltyrosine Bip L-BiphenylalanineS(Bzl) L-O-Benzylserine T(Bzl) L-O-Benzylthreonine hChaL-Homo-cyclohexylalanine hCys L-Homo-cysteine hSer L-Homo-serine hArgL-Homo-arginine hPhe L-Homo-phenylalanine Bpa L-4-BenzoylphenylalaninePip L-Pipecolic acid OctG L-Octylglycine MePhe L-N-MethylphenylalanineMeNle L-N-Methylnorleucine MeAla L-N-Methylalanine MeIleL-N-Methylisoleucine MeVal L-N-Methvaline MeLeu L-N-Methylleucine

[0480] In addition, the most preferred values for B also include groupsof type A8″ of (L)-configuration:

[0481] wherein R²⁰ is H or lower alkyl and R⁶⁴ is alkyl; alkenyl; aryl;aryl-lower alkyl; or heteroaryl-lower alkyl; especially those whereinR⁶⁴ is n-hexyl (A8″-21); n-heptyl (A8″-22); 4-(phenyl)benzyl (A8″-23);diphenylmethyl (A8″-24); 3-amino-propyl (A8″-25); 5-amino-pentyl(A8″-26); methyl (A8″-27); ethyl (A8″-28); isopropyl (A8″-29); isobutyl(A8″-30); n-propyl (A8″-31); cyclohexyl (A8″-32); cyclohexyhnethyl(A8″-33); n-butyl (A8″-34); phenyl (A8″-35); benzyl (A8″-36),(3-indolyl)methyl (A8″-37); 2-(3-indolyl)ethyl (A8″-38);(4-phenyl)phenyl (A8″-39); and n-nonyl (A8″-40).

[0482] The peptidic chains Z, Z¹ and Z² of the β-hairpin mimeticsdescribed herein are generally defined in terms of amino acid residuesbelonging to one of the following groups:

[0483] Group C —NR²⁰CH(R⁷²)CO—; “hydrophobic: small to medium-sized”

[0484] Group D —NR²⁰CH(R⁷³)CO—; “hydrophobic: large aromatic orheteroarornatic”

[0485] Group E —NR²⁰CH(R⁷⁴)CO—; “polar-cationic”, “acylamino” and“urea-derived”

[0486] Group F —NR²⁰CH(R⁸⁴)CO—; “polar-non-charged”

[0487] Group H —NR²⁰—CH(CO—)—(CH₂)₄₋₇—CH(CO—)—NR²⁰—;

[0488] —NR²⁰—CH(CO—)—(CH₂)_(p)SS(CH₂)_(p)—CH(CO—)—NR²⁰—;

[0489] —NR²⁰—CH(CO—)—(—(CH₂)_(p)NR²⁰CO(CH₂)_(p) —CH(CO—)—NR²⁰—; and

[0490] —NR²⁰—CH(CO—)—(—(CH₂)_(p)CONR²⁰(CH₂)_(p)—CH(CO—)—NR²⁰—;

[0491] “interstrand linkage”

[0492] Furthermore, the amino acid residues in chains Z, Z¹ and Z² canalso be of formula -A-CO— or of formula —B—CO— wherein A and B are asdefined above. Finally, Gly can also be an amino acid residue in chainsZ, Z¹ and Z², and Pro can be an amino acid residue in chains Z, Z¹ andZ², too, with the exception of positions where interstrand linkages (E)are possible.

[0493] Group C comprises amino acid residues with small to medium-sizedhydrophobic side chain groups according to the general definition forsubstituent R⁷². A hydrophobic residue refers to an amino acid sidechain that is uncharged at physiological pH and that is repelled byaqueous solution. Furthermore these side chains generally do not containhydrogen bond donor groups, such as (but not limited to) primary andsecondary amides, primary and secondary amines and the correspondingprotonated salts thereof, thiols, alcohols, phosphonates, phosphates,ureas or thioureas. However, they may contain hydrogen bond acceptorgroups such as ethers, thioethers, esters, tertiary amides, alkyl- oraryl phosphonates and phosphates or tertiary amines. Genetically encodedsmall-to-medium-sized amino acids include alanine, isoleucine, leucine,methionine and valine.

[0494] Group D comprises amino acid residues with aromatic andheteroaromatic side chain groups according to the general definition forsubstituent R⁷³. An aromatic amino acid residue refers to a hydrophobicamino acid having a side chain containing at least one ring having aconjugated π-electron system (aromatic group). In addition they maycontain hydrogen bond donor groups such as (but not limited to) primaryand secondary amides, primary and secondary amines and the correspondingprotonated salts thereof, thiols, alcohols, phosphonates, phosphates,ureas or thioureas, and hydrogen bond acceptor groups such as (but notlimited to) ethers, thioethers, esters, tetriary amides, alkyl- or arylphosphonates and phosphates or tertiary amines. Genetically encodedaromatic amino acids include phenylalanine and tyrosine.

[0495] A heteroaromatic amino acid residue refers to a hydrophobic aminoacid having a side chain containing at least one ring having aconjugated π-system incorporating at least one heteroatom such as (butnot limited to) O, S and N according to the general definition forsubstituent R⁷⁷. In addition such residues may contain hydrogen bonddonor groups such as (but not limited to) primary and secondary amides,primary and secondary amines and the corresponding protonated saltsthereof, thiols, alcohols, phosphonates, phosphates, ureas or thioureas,and hydrogen bond acceptor groups such as (but not limited to) ethers,thioethers, esters, tetriary amides, alkyl- or aryl phosphonates andphosphates or tertiary amines. Genetically encoded heteroaromatic aminoacids include tryptophan and histidine.

[0496] Group E comprises amino acids containing side chains withpolar-cationic, acylamino- and urea-derived residues according to thegeneral definition for substituen R⁷⁴. Polar-cationic refers to a basicside chain which is protonated at physiological pH. Genetically encodedpolar-cationic amino acids include arginine, lysine and histidine.Citrulline is an example for an urea derived amino acid residue.

[0497] Group F comprises amino acids containing side chains withpolar-non-charged residues according to the general definition forsubstituent R⁸⁴. A polar-non-charged residue refers to a hydrophilicside chain that is uncharged at physiological pH, but that is notrepelled by aqueous solutions. Such side chains typically containhydrogen bond donor groups such as (but not limited to) primary andsecondary amides, primary and secondary amines, thiols, alcohols,phosphonates, phosphates, ureas or thioureas. These groups can formhydrogen bond networks with water molecules. In addition they may alsocontain hydrogen bond acceptor groups such as (but not limited to)ethers, thioethers, esters, tetriary amides, alkyl- or aryl phosphonatesand phosphates or tertiary amines. Genetically encoded polar-non-chargedamino acids include asparagine, cysteine, glutamine, serine andthreonine.

[0498] Group H comprises side chains of preferably (L)-amino acids atopposite positions of the β-strand region that can form an interstrandlinkage. The most widely known linkage is the disulfide bridge formed bycysteines and homo-cysteines positioned at opposite positions of theβ-strand. Various methods are known to form disulfide linkages includingthose described by: J. P. Tam et al. Synthesis 1979, 955-957; Stewart etal., Solid Phase Peptide Synthesis, 2d Ed., Pierce Chemical Company,III., 1984; Ahmed et al. J. Biol. Chem. 1975, 250, 8477-8482; andPennington et al., Peptides, pages 164-166, Giralt and Andreu, Eds.,ESCOM Leiden, The Netherlands, 1990. Most advantageously, for the scopeof the present invention, disulfide linkages can be prepared asdescribed hereinafter in the pertinent Examples (procedure 3), usingacetamidomethyl (Acm)—protective groups for cysteine. A well establishedinterstrand linkage consists in linking ornithines and lysines,respectively, with glutamic and aspartic acid residues located atopposite β-strand positions by means of an amide bond formation.Preferred protective groups for the side chain amino-groups of ornithineand lysine are allyloxycarbonyl (Alloc) and allylesters for aspartic andglutamic acid as described hereinafter in the pertinent Examples(procedure 4). Finally, interstrand linkages can also be established bylinking the amino groups of lysine and omithine located at oppositeβ-strand positions with reagents such as N,N-arbonylimidazole to formcyclic ureas.

[0499] As mentioned earlier, positions for interstrand linkages are thefollowing:

[0500] If n=8: Positions P2 and n taken together,

[0501] if n=9: Positions P2 and P8 taken together,

[0502] if n=10:Positions P3 and P8 taken together,

[0503] if n=11:Positions P4 and P8; and/or P2 and P10 taken together;

[0504] if n=12:Positions P4 and P9; and/or P2 and P11 taken together,

[0505] if n=13:Positions P4 and P10; and/or Positions P2 and P12 takentogether;

[0506] if n=14:Positions P5 and P10; and/or P3 and P12 taken together;and

[0507] if n=15:Positions P6 and P10; and/or P4 and P12; and/or n andP14.

[0508] if n=16:Positions P6 and P11; and/or P4 and P13; and/or P2 andP15 taken together.

[0509] Such interstrand linkages are known to stabilize the β-hairpinconformations and thus constitute an important structural element forthe design of β-hairpin mimetics.

[0510] Most preferred amino acid residues chains Z, Z¹ and Z² are thosederived from natural α-amino acids. Hereinafter follows a list of aminoacids which, or the residues of which, are suitable for the purposes ofthe present invention, the abbreviations corresponding to generallyadopted usual practice: three letter code one letter code Ala L-AlanineA Arg L-Arginine R Asn L-Asparagine N Asp L-Aspartic acid D CysL-Cysteine C Glu L-Glutamic acid E Gln L-Glutamine Q Gly Glycine G HisL-Histidine H Ile L-Isoleucine I Leu L-Leucine L Lys L-Lysine K MetL-Methionine M Phe L-Phenylalanine F Pro L-Proline P ^(D)Pro D-Proline^(D)P Ser L-Serine S Thr L-Threonine T Trp L-Tryptophan W Tyr L-TyrosineY Val L-Valine V

[0511] Other α-amino acids which, or the residues of which, are suitablefor the purposes of the present invention include: Cit L-Citrulline OrnL-Ornithine tBuA L-t-Butylalanine Sar Sarcosine Pen L-Penicillaminet-BuG L-tert-Butylglycine 4AmPhe L-para-Aminophenylalanine 3AmPheL-meta-Aminophenylalanine 2AmPhe L-ortho-AminophenylalaninePhe(mC(NH₂)═NH) L-meta-Amidinophenylalanine Phe(pC(NH₂)═NH)L-para-Amidinophenylalanine Phe(mNHC (NH₂)═NH)L-meta-Guanidinophenylalanine Phe(pNHC (NH₂)═NH)L-para-Guanidinophenylalanine Phg L-Phenylglycine ChaL-Cyclohexylalanine C₄al L-3-Cyclobutylalanine C₅alL-3-Cyclopentylalanine Nle L-Norleucine 2-Nal L-2-Naphthylalanine 1-NalL-1-Naphthylalanine 4Cl-Phe L-4-Chlorophenylalanine 3Cl-PheL-3-Chlorophenylalanine 2Cl-Phe L-2-Chlorophenylalanine 3,4Cl₂-PheL-3,4-Dichlorophenylalanine 4F-Phe L-4-Fluorophenylalanine 3F-PheL-3-Fluorophenylalanine 2F-Phe L-2-Fluorophenylalanine Tic1,2,3,4-Tetrahydroisoquinoline-3- carboxylic acid ThiL-β-2-Thienylalanine Tza L-2-Thiazolylalanine Mso L-Methionine sulfoxideAcLys N-Acetyllysine Dpr 2,3-Diaminopropionic acid A₂Bu2,4-Diaminobutyric acid Dbu (S)-2,3-Diaminobutyric acid Abuγ-Aminobutyric acid (GABA) Aha ε-Aminohexanoic acid Aibα-Aminoisobutyric acid Y(Bzl) L-O-Benzyltyrosine BipL-(4-phenyl)phenylalanine S(Bzl) L-O-Benzylserine T(Bzl)L-O-Benzylthreonine hCha L-Homo-cyclohexylalanine hCys L-Homo-cysteinehSer L-Homo-serine hArg L-Homo-arginine hPhe L-Homo-phenylalanine BpaL-4-Benzoylphenylalanine 4-AmPyrr1(2S,4S)-4-Amino-pyrrolidine-L-carboxylic acid 4-AmPyrr2(2S,4R)-4-Amino-pyrrolidine-L-carboxylic acid 4-PhePyrr1(2S,5R)-4-Phenyl-pyrrolidine-L-carboxylic acid 4-PhePyrr2(2S,5S)-4-Phenyl-pyrrolidine-L-carboxylic acid 5-PhePyrr1(2S,5R)-5-Phenyl-pyrrolidine-L-carboxylic acid 5-PhePyrr2(2S,5S)-5-Phenyl-pyrrolidine-L-carboxylic acid Pro(4-OH)1(4S)-L-Hydroxyproline Pro(4-OH)2 (4R)-L-Hydroxyproline Pip L-Pipecolicacid ^(D)Pip D-Pipecolic acid OctG L-Octylglycine MePheL-N-Methylphenylalanine MeNle L-N-Methylnorleucine MeAlaL-N-Methylalanine MeIle L-N-Methylisoleucine MeVal L-N-MethylvalineMeLeu L-N-Methylleucine

[0512] Particularly preferred residues for group C are: Ala L-AlanineIle L-Isoleucine Leu L-Leucine Met L-Methionine Val L-Valine tBuAL-t-Butylalanine t-BuG L-tert-Butylglycine Cha L-Cyclohexylalanine C₄alL-3-Cyclobutylalanine C₅al L-3-Cyclopentylalanine Nle L-Norleucine hChaL-Homo-cyclohexylalanine OctG L-Octylglycine MePheL-N-Methylphenylalanine MeNle L-N-Methylnorleucine MeAlaL-N-Methylalanine MeIle L-N-Methylisoleucine MeVal L-N-MethylvalineMeLeu L-N-Methylleucine

[0513] Particularlily preferred residues for group D are: HisL-Histidine Phe L-Phenylalanine Trp L-Tryptophan Tyr L-Tyrosine PhgL-Phenylglycine 2-Nal L-2-Naphthylalanine 1-Nal L-1-Naphthylalanine4Cl-Phe L-4-Chlorophenylalanine 3Cl-Phe L-3-Chlorophenylalanine 2Cl-PheL-2-Chlorophenylalanine 3,4Cl₂-Phe L-3,4-Dichlorophenylalanine 4F-PheL-4-Fluorophenylalanine 3F-Phe L-3-Fluorophenylalanine 2F-PheL-2-Fluorophenylalanine Thi L-β-2-Thienylalanine TzaL-2-Thiazolylalanine Y(Bzl) L-O-Benzyltyrosine Bip L-BiphenylalanineS(Bzl) L-O-Benzylserine T(Bzl) L-O-Benzylthreonine hPheL-Homo-phenylalanine Bpa L-4-Benzoylphenylalanine

[0514] Particularly preferred residues for group E are Arg L-ArginineLys L-Lysine Orn L-Ornithine Dpr L-2,3-Diaminopropionic acid A₂BuL-2,4-Diaminobutyric acid Dbu (S)-2,3-Diaminobutyric acid Phe(pNH₂)L-para-Aminophenylalanine Phe(mNH₂) L-meta-Aminophenylalanine Phe(oNH₂)L-ortho-Aminophenylalanine hArg L-Homo-arginine Phe(mC(NH₂)═NH)L-meta-Amidinophenylalanine Phe(pC(NH₂)═NH) L-para-AmidinophenylalaninePhe(mNHC (NH₂)═NH) L-meta-Guanidinophenylalanine Phe(pNHC (NH₂)═NH)L-para-Guanidinophenylalanine Cit L-Citrulline

[0515] Particularly preferred residues for group F are Asn L-AsparagineCys L-Cysteine Glu L-Glutamine Ser L-Serine Thr L-Threonine CitL-Citrulline Pen L-Penicillamine AcLys L-N^(ε)-Acetyllysine hCysL-Homo-cysteine hSer L-Homo-serine

[0516] In the dimeric structures Ib the preferred substituents forminggroups G1 and G2 are the following, with the proviso that R³³ is lowerallyl; or lower alkenyl; R³⁴ is H; or lower alkyl; and R⁶¹ is H:

[0517] R²: —(CH₂)_(m)O—; —(CH₂)_(o)NR³³R³⁴—; —(CH₂)_(o)CO—

[0518] R⁵: —(CH₂)_(o)O—; —(CH₂)_(o)NR³³R³⁴—; —(CH₂)_(o)CO—

[0519] R⁶: —(CH₂)_(o)O—; —(CH₂)_(o)NR³³R³⁴—; —(CH₂)_(o)CO—

[0520] R⁸: —(CH₂)_(o)O—; —(CH₂)_(o)NR³³R³⁴—; —(CH₂)_(o)CO—

[0521] R⁹: —(CH₂)_(o)O—; —(CH₂)_(o)NR³³R³⁴—; —(CH₂)_(o)CO—

[0522] R¹⁰: —(CH₂)_(o)O—; —(CH₂)_(o)NR³³R³⁴—; —(CH₂)_(o)CO—

[0523] R¹¹: —(CH₂)_(m)O—; —(CH₂)_(m)NR³³R³⁴—; —(CH₂)_(o)CO—

[0524] R¹⁴: —(CH₂)_(m)O—; —(CH₂)_(m)NR³³R³⁴—; —(CH₂)_(o)CO—

[0525] R¹⁵: —(CH₂)_(m)O—; —(CH₂)_(m)R³³R³⁴—; —(CH₂)_(o)CO—

[0526] R¹⁶: —(CH₂)_(m)O—; —(CH₂)_(m)NR³³R³⁴—; —(CH₂)_(o)CO—

[0527] R¹⁸: —(CH₂)_(p)O—; —(CH₂)_(p)NR³³R³⁴—; —(CH₂)_(p)CO_

[0528] R¹⁹: —(CH₂)_(p)O—; —(CH₂)_(p)NR³³R³⁴—; —(CH₂)_(p)CO—

[0529] R²¹: —(CH₂)_(o)O—; —(CH₂)_(o)NR³³R³⁴—; —(CH₂)_(o)CO—

[0530] R²³: —(CH₂)_(o)O—; —(CH₂)_(o)R³³R³⁴; —(CH₂)_(s)CO—

[0531] R²⁴: —(CH₂)_(o)O—, —(CH₂)_(o)NR³³R³⁴—; —(CH₂)_(o)CO—

[0532] R²⁵: —(CH₂)_(m)O—; —(CH₂)_(m)NR³³R³⁴—; —(CH₂)_(o)CO—

[0533] R²⁶: —(CH₂)_(m)O—; —(CH₂)_(m)NR³³R³⁴—; —(CH₂)_(o)CO—

[0534] R²⁸: —(CH₂)_(o)O—; —(CH₂)_(o)NR³³R³⁴—; —(CH₂)_(o)CO—

[0535] R²⁹: —(CH₂)_(o)O—; —(CH₂)_(o)NR³³R³⁴—; —(CH₂)_(o)CO—

[0536] R³¹: —(CH₂)_(p)O—; —(CH₂)_(p)NR³³R³⁴—; —(CH₂)_(p)CO—

[0537] R³⁷: —(CH₂)_(p)O—; —(CH₂)_(p)R³³R³⁴—; —(CH₂)_(o)CO—

[0538] R³⁸: —(CH₂)_(p)O—; —(CH₂)_(p)R³³R³⁴—; —(CH₂)_(o)CO—

[0539] R⁴¹: —(CH₂)_(p)O—; —(CH₂)_(p)NR³³R³⁴—; —(CH₂)_(o)CO—

[0540] R⁴²: —(CH₂)_(p)O—; —(CH₂)_(p)NR³³R³⁴—; —(CH₂)_(o)CO—

[0541] R⁴⁵: —(CH₂)_(o)O—; —(CH₂)_(o)NR³³R³⁴; —(CH₂)_(s)CO—

[0542] R⁴⁷: —(CH₂)_(o)O—

[0543] R⁴⁹: —(CH₂)_(s)O—; —(CH₂)_(s)CO—

[0544] R⁵¹: —(CH₂)_(m)O—; —(CH₂)_(m)NR³³R³⁴—; —(CH₂)_(o)CO—

[0545] R⁵²: —(CH₂)_(m)O—; —(CH₂)_(m)NR³³R³⁴—; —(CH₂)_(o)CO—

[0546] R⁵³: —(CH₂)_(m)O—; —(CH₂)_(m)NR³³R³⁴—; —(CH₂)_(o)CO—

[0547] and with the further provisos that the preferred linker moleculesL are as defined below, that R³⁴ is H; or lower alkyl; X is O; S; NR³⁴;—NR³⁴CONR³⁴; or —OCOO—; and Y is C₆R⁶⁷R⁶⁸R⁶⁹R⁷⁰;

[0548] L1: —(CH₂)_(p)[X(CH₂)_(p)]_(o)—

[0549] L2: —CO(CH₂)_(p)[X(CHR²)_(p)]_(o)CO—

[0550] L3: —CONR³⁴(CH₂)_(p)[X(CH₂)_(p)]_(o)NR³⁴CO—

[0551] L4: —O(CH₂)_(p)[X(CH₂)_(p)]_(o)O—

[0552] L6: —NR³⁴(CH₂)_(p)[X(CH₂)_(p)]_(o)NR³⁴—

[0553] L7: —(CH₂)_(o)Y(CH₂)_(o)—

[0554] L8: —CO(CH₂)_(o)Y(CH₂)_(o)CO—

[0555] L9: CONR³⁴(CH₂)_(o)Y(CH₂)_(o)NR³CO—

[0556] L10: —O(CH₂)_(o)Y(CH₂)_(o)O—

[0557] L11:—S(CH₂)_(o)Y(CH₂)_(o)S—

[0558] L12: —NR³⁴(CH₂)_(o)Y(CH₂)_(o)NR³⁴—

[0559] L13:—CO(CH₂)_(p)[X(CH₂)_(p)]_(o)NR³⁴—

[0560] L14:—CO(CH₂)_(o)Y(CH₂)_(o)NR³⁴—

[0561] L15—NR³⁴(CH₂)_(p)[X(CH₂)_(p)]_(o)CO—

[0562] L16—NR³⁴(CH₂)_(o)Y(CH₂)_(o)CO—

[0563] with the proviso that

[0564] —(CH₂)_(m)O— can be combined with linker L1, L2, L3, L7, L8 orL9;

[0565] —(CH₂)_(o)O— can be combined with linker L1, L2, L3, L7, L8 orL9;

[0566] —(CH₂)_(p)O— can be combined with linker L1, L2, L3, L7, L8 orL9;

[0567] —(CH₂)_(s)O— can be combined with linker L1, L2, L3, L7, L8 orL9;

[0568] —(CH₂)_(m)NR³⁴— can be combined with liker L, L2, L3, L7, L8 orL9;

[0569] —(CH₂)_(o)NR³⁴— can be combined with linker L1, L2, L3, L7, L8 orL9;

[0570] —(CH₂)_(p)NR³⁴— can be combined with linker L1, L2, L3, L7, L8 orL9;

[0571] —(CH₂)_(o)CO— can be combined with linker L4, L5, L6, L10, L11 orL12;

[0572] —(CH₂)_(p)CO— can be combined with linker L4, L5, L6, L10, L11 orL12;

[0573] —(CH₂)_(s)CO— can be combined with linker L4, L5, L6, L10, L11 orL12;

[0574] —(CH₂)_(m)O— can be combined with linker L13 or L14 and theresulting combination with

[0575] —(CH₂)_(o)CO—; —(CH₂)_(p)CO—; or —(CH₂)_(s)CO—;

[0576] —(CH₂)_(p)O— can be combined with linker L13 or L14 and theresulting combination with

[0577] —(CH₂)_(s)CO—; —(CH₂)_(p)CO—; or —(CH₂)_(s)CO—;

[0578] (CH₂)_(p)m— can be combined with linker L13 or L14 and theresulting combination with

[0579] —(CH₂)_(o)CO—; —(CH₂)_(p)CO—; or —(CH₂)_(s)CO—;

[0580] —(CH₂)_(o)O— can be combined with linker L13 or L14 and theresulting combination with

[0581] —(CH₂)_(o)CO—; —(CH₂)_(p)CO—; or —(CH₂)_(s)CO—;

[0582] —(CH₂)_(o)NR³⁴— can be combined with linker L13 or L14 and theresulting combination with

[0583] —(CH₂)_(o)CO—; —(CH₂)_(p)CO—; or —(CH₂)_(s)CO—;

[0584] —(CH₂)_(o)NR³⁴— can be combined with linker L13 or L14 and theresulting combination with

[0585] —(CH₂)_(o)CO—; —(CH₂)_(p)CO—; or —(CH₂)_(s)CO—;

[0586] —(CH₂)_(p)NR³⁴— can be combined with linker L13 or L14 and theresulting combination with

[0587] —(CH₂)_(o)CO—; —(CH₂)_(p)CO—; or —(CH₂)_(s)CO—;

[0588] —(CH₂)_(o)CO— can be combined with linker L15 or L16 and theresulting combination with

[0589] —(CH₂)_(m)X—; —(CH₂)_(o)X—; —(CH₂)_(p)X—; or —(CH₂)_(q)—;

[0590] —(CH₂)_(p)CO— can be combined with linker L15 or L16 and theresulting combination with

[0591] —(CH₂)_(m)X—; —(CH₂)_(o)X—; —(CH₂)_(p)X—; or —(CH₂)_(q)X—;

[0592] —(CH₂)_(s)CO— can be combined with linker L15 or L16 and theresulting combination with

[0593] —(CH₂)_(m)X—; —(CH₂)_(o)X—; —(CH₂)_(p)X—; or —(CH₂)_(q)X—.

[0594] Generally, the peptidic chain Z, Z¹ or Z² within the β-hairpinmimetics of the invention comprises 8-16 amino acid residues (n=8-16).The positions P¹ to P^(n) of each amino acid residue in the chain Z, Z¹or Z² are unequivocally defined as follows: P¹ represents the firstamino acid in the chain Z, Z¹ or Z² that is coupled with its N-terminusto the C-terminus of the templates (b)-(p) or of group —B—CO— intemplate (a1), or of group -A-CO— in template a2, and P^(n) representsthe last amino acid in the chain Z, Z¹ or Z² that is coupled with itsC-terminus to the N-terminus of the templates (b)-(p) or of group -A-CO—in template (a1) or of group —B—CO— in template (a2). Each of thepositions P¹ to P^(n) will preferably contain an amino acid residuebelonging to one or two of above types C to F, as follows:

[0595] If n is 8, the amino acid residues in position 1-8 arepreferably:

[0596] P1: of type C or of type D; or of type E;

[0597] P2: of type E; or of type D;

[0598] P3: of type E;

[0599] P4: of type E or of formula -A1-A69-CO—;

[0600] P5: of type E or of formula —B—CO—;

[0601] P6: of type D;

[0602] P7: of type E; or of type D and

[0603] P8: of type C or of type D; or of type E;

[0604] at P4 and P5 also D-isomers being possible;

[0605] if n is 9, the amino acid residues in position 1-9 arepreferably:

[0606] P1: of type C or of type D; or of type E;

[0607] P2: of type E; or of type D;

[0608] P3: of type C;

[0609] P4: of type E, or the residue is Pro;

[0610] P5: of type E, or the residue is Pro;

[0611] P6: of type D or of type E, or the residue is Pro;

[0612] P7: of type E or of type D;

[0613] P8: of type E; or of type D and

[0614] P9: of type C or of type D; or of type E;

[0615] at P4, P5 and P6 also D isomers being possible;

[0616] if n is 10, the amino acid residues in position 1-10 arepreferably:

[0617] P1: of type C or of type D; or of type E;

[0618] P2: of type E; or of type D;

[0619] P3: of type C;

[0620] P4: of type E or of type D;

[0621] P5: of type E or of formula -A1-A69CO—;

[0622] P6: of type E or of formula —B—CO—;

[0623] P7: of type D or of type E;

[0624] P8: of type D;

[0625] P9: of type E; or of type D and

[0626] P10: of type C or of type D; or of type E;

[0627] at P5 and P6 also D-isomers being possible;

[0628] if n is 11, the amino acid residues in position 1-11 arepreferably:

[0629] P1: of type C or of type D; or of type E;

[0630] P2: of type E; or of type D;

[0631] P3: of type D;

[0632] P4: of type E or of type C;

[0633] P5: of type E, or the residue is Pro;

[0634] P6: of type E, or the residue is Pro;

[0635] P7: of type E, or the residue is Pro;

[0636] P8: of type D or of type E;

[0637] P9: of type D;

[0638] P10: of type E; or of type D and

[0639] P11: of type C or of type D; or of type E;

[0640] at P5, P6 and P7 also D-isomers being possible;

[0641] if n is 12, the amino acid residues in position 1-12 arepreferably:

[0642] P1: of type C or of type E; or of type D; or of type F;

[0643] P2: of type E; or of type D;

[0644] P3: of type C or of type D;

[0645] P4: of type E;

[0646] P5: of type E; or of type C;

[0647] P6: of type E or of type F or of formula -A1-A69-CO—;

[0648] P7: of type E or of formula —B—CO—;

[0649] P8: of type D;

[0650] P9: of type E or of ype D;

[0651] P10: of type D;

[0652] P11: of type E; or of type D and

[0653] P12: of type C or of type E; or of type D; or of type F;

[0654] at P6 and P7 also D-isomers being possible;

[0655] if n is 13, the amino acid residues in position 1-13 arepreferably:

[0656] P1: of type C or of type D; or of type E;

[0657] P2: of type E; or of type D;

[0658] P3: of type C or of type D;

[0659] P4: of type E or of type C;

[0660] P5: of type E or of type D;

[0661] P6: of type E or of type F, or the residue is Pro;

[0662] P7: of type E, or the residue is Pro;

[0663] P8: of type D, or the residue is Pro;

[0664] P9: of type D;

[0665] P10: of type E or of type C;

[0666] P11: of type C or of type D;

[0667] P12: of type E; or of type D and

[0668] P13: of type C or of type D; or of type E;

[0669] at P6, P7 and P8 also D-isomers being possible;

[0670] if n is 14, the amino acid residues in position 1-14 arepreferably:

[0671] P1: of type C or of type D; or of type E;

[0672] P2: of type E; or of type D;

[0673] P3: of type C or of type D;

[0674] P4: of type D;

[0675] P5: of type E;

[0676] P6: of type E;

[0677] P7: of type E or of type F or of formula -A1-A69-CO—;

[0678] P8: of type E or of formula —B—CO—;

[0679] P9: of type D;

[0680] P10: of type C;

[0681] P11: of type E or of type D;

[0682] P12: of type D or of type C;

[0683] P13: of type E; or of type D and

[0684] P14: of type C or of type D; or of type E;

[0685] at P7 and P8 also D-isomers being possible;

[0686] if n is 15, the amino acid residues in position 1-15 arepreferably:

[0687] P1: of type C and of type D; or of type E;

[0688] P2: of type E; or of type D;

[0689] P3: of type C and of type D;

[0690] P4: of type E or of type C;

[0691] P5: of type C;

[0692] P6: of type E or of type D;

[0693] P7: of type C, or the residue is Pro;

[0694] P8: of type E or of type F, or the residue is Pro;

[0695] P9: of type E or of type F, or the residue is Pro;

[0696] P10: of type E;

[0697] P11: of type C;

[0698] P12: of type E or of type C;

[0699] P13: of type D or of type C;

[0700] P14: of type E; or of type D and

[0701] P15: of type C and of type D; or of type E;

[0702] at P7, P8 and P9 also D-isomers being possible; and

[0703] if n is 16, the amino acid residues in position 1-16 arepreferably:

[0704] P1: of type D; or of type E;

[0705] P2: of type E; or of type D;

[0706] P3: of type C or of type D;

[0707] P4: of type E or of type D;

[0708] P5: of type D;

[0709] P6: of type E;

[0710] P7: of type E or of type F;

[0711] P8: of type E or of type F or of formula -A1-A69-CO—;

[0712] P9: of type E or of formula —B—CO—;

[0713] P10: of type D;

[0714] P11: of type E;

[0715] P12: of type D;

[0716] P13: of type E or of type C;

[0717] P14: of type C or of type D;

[0718] P15: of type E; or of type D and

[0719] P16: of type C or of type D; or of type E;

[0720] at P8 and P9 also D-isomers being possible.

[0721] If n is 12, the amino acid residues in position 1-12 are mostpreferably:

[0722] P1: Leu; Arg; Lys; Tyr; Trp; Val; Gln; or 4-AmPhe;

[0723] P2: Arg; Trp; or Gln;

[0724] P3: Leu; Val; Ile; or Phe;

[0725] P4: Lys; Arg; Gln; or Orn;

[0726] P5: Lys; or Arg,

[0727] P6: Arg; Y(Bzl); or ^(D)Y(Bzl);

[0728] P7: Arg;

[0729] P8: Trp; Bip; 1-Nal; Y(Bzl); or Val;

[0730] P9: Lys; Arg; orn; Tyr, Trp; or Gln;

[0731] P10: Tyr; T(Bzl); or Y(Bzl);

[0732] P11: Arg; or Tyr; and

[0733] P12: Val; Arg; 1-Nal; or 4-AmPhe.

[0734] Particularly preferred β-peptidomimetics of the invention includethose described in Examples 106, 137, 161, 197, 206, 222, 230, 250, 256,267, 277, 281, 283, 284, 285, 286, 289, 294, 295, 296, 297, and 298.

[0735] The process of the invention can advantageously be carried out asparallel array synthesis to yield libraries of template-fixed β-hairpinpeptidomimetics of the above general formula I. Such parallel synthesisallows one to obtain arrays of numerous (normally 24 to 192, typically96) compounds of general formula I in high yields and defined purities,minimizing the formation of dimeric and polymeric by-products. Theproper choice of the functionalized solid-support (i.e. solid supportplus linker molecule), templates and site of cyclization play therebykey roles.

[0736] The functionalized solid support is conveniently derived frompolystyrene crosslinked with, preferably 1-5%, divinylbenzene;polystyrene coated with polyethyleneglycol spacers (Tentagel^(R)); andpolyacrylamide resins (see also Obrecht, D.; Villalgordo, J.-M, “Solid-Supported Combinatorial and Parallel Synthesis of Small-Molecular-WeightCompound Libraries”, Tetrahedron Organic Chemistry Series, Vol. 17,Pergamon, Elsevier Science, 1998).

[0737] The solid support is functionalized by means of a linker, i.e. abifunctional spacer molecule which contains on one end an anchoringgroup for attachment to the solid support and on the other end aselectively cleavable functional group used for the subsequent chemicaltransformations and cleavage procedures. For the purposes of the presentinvention the linker must be designed to eventually release the carboxylgroup under mild acidic conditions which do not affect protecting groupspresent on any functional group in the side-chains of the various aminoacids. Linkers which are suitable for the purposes of the presentinvention form acid-labile esters with the carboxyl group of the aminoacids, usually acid-labile benzyl benzhydryl and trityl esters; examplesof linker structures of this kind include2-methoxy-4-hydroxymethylphenoxy (Sasrin^(R) linker),4-(2,4-dimethoxyphenyl-hydroxymethyl)-phenoxy (Rink linker),4-(4-hydroxymethyl-3-methoxyphenoxy)butyric acid (HMOB linker), trityland 2-chlorotrityl.

[0738] Preferably, the support is derived from polystyrene crosslinkedwith, most preferably 1-5%, divinylbenzene and functionalized by meansof the 2-chlorotrityl linker.

[0739] When carried out as a parallel array synthesis the process of theinvention can be advantageously carried out as described hereinbelow butit will be immediately apparent to those skilled in the art how thisprocedure will have to be modified in case it is desired to synthesizeone single compound of the above formula Ia or Ib.

[0740] A number of reaction vessels (normally 24 to 192, typically 96)equal to the total number of compounds to be synthesized by the parallelmethod are loaded with 25 to 1000 mg, preferably 100 mg, of theappropriate functionalized solid support, preferably 1 to 3% crosslinked polystyrene or tentagel resin.

[0741] The solvent to be used must be capable of swelling the resin andincludes, but is not limited to, dichloromethane (DCM),dimethylformamide (DMF), N-methylpyrrolidone (NMP), dioxane, toluene,tetrahydrofuran (THF), ethanol (EtOH), trifluoroethanol (TFE),isopropylalcohol and the like. Solvent mixtures containing as at leastone component a polar solvent (e.g. 20% TFE/DCM, 35% THF/NMP) arebeneficial for ensuring high reactivity and solvation of the resin-boundpeptide chains (Fields, G. B., Fields, C. G., J. Am. Chem. Soc. 1991,113, 4202-4207).

[0742] With the development of various linkers that release theC-terminal carboxylic acid group under mild acidic conditions, notaffecting acid-labile groups protecting functional groups in the sidechain(s), considerable progresses have been made in the synthesis ofprotected peptide fragments. The 2-methoxy4-hydroxybenzylalcohol-derivedlinker (Sasrin^(R) linker, Mergler et al., Tetrahedron Lett. 1988, 2940054008) is cleavable with diluted trifluoroacetic acid (0.5-1% TFA inDCM) and is stable to Fmoc deprotection conditions during the peptidesynthesis, Boc/tBu-based additional protecting groups being compatiblewith this protection scheme. Other linkers which are suitable for theprocess of the invention include the super acid labile4-(2,4-dimethoxyphenyl-hydroxymethyl)-phenoxy linker (Rink linker, Rink,H. Tetrahedron Lett. 1987, 28, 3787-3790), where the removal of thepeptide requires 10% acetic acid in DCM or 0.2% trifluoroacetic acid inDCM; the 4-(4-hydroxymethyl-3-methoxyphenoxy)butyric acid-derived linker(HMPB-linker, Florsheimer & Riniker, Peptides 1991, 1990 131) which isalso cleaved with 1% TFA/DCM in order to yield a peptide fragmentcontaining all acid labile side-chain protective groups; and, inaddition, the 2-chlorotritylchloride linker (Barlos et al., TetrahedronLets. 1989, 30, 3943-3946), which allows the peptide detachment using amixture of glacial acetic acid/trifluoroethanoV/DCM (1:2:7) for 30 min.

[0743] Suitable protecting groups for amino acids and, respectively, fortheir residues are, for example,

[0744] for the amino group (as is present e.g. also in the side-chain oflysine) Cbz benzyloxycarbonyl Boc tert.-butyloxycarbonyl Fmoc9-fluorenylmethoxycarbonyl Alloc allyloxycarbonyl Teoctrimethylsilylethoxycarbonyl Tcc trichloroethoxycarbonyl Npso-nitrophenylsulfonyl; Trt triphenymethyl or trityl

[0745] for the carboxyl group (as is present e.g. also in the side-chainof aspartic and glutamic acid) by conversion into esters with thealcohol components tBu tert.-butyl Bn benzyl Me methyl Ph phenyl PacPhenacyl Allyl Tse trimethylsilylethyl Tce trichloroethyl;

[0746] for the guanidino group (as is present e.g. in the side-chain ofarginine) Pmc 2,2,5,7,8-pentamethylchroman-6-sulfonyl Ts tosyl (i.e.p-toluenesulfonyl) Cbz benzyloxycarbonyl Pbfpentamethyldihydrobenzofuran-5-sulfonyl

[0747] for the hydroxy group (as is present e.g. in the side-chain ofthreonine and serine) tBu tert.-butyl Bn benzyl Trt trityl

[0748] and for the mercapto group (as is present e.g. in the side-chainof cysteine) Acm acetamidomethyl tBu tert.-butyl Bn benzyl Trt tritylMtr 4-methoxytrityl.

[0749] The 9-fluorenylmethoxycarbonyl-(Fmoc)-protected amino acidderivatives are preferably used as the building blocks for theconstruction of the template-fixed β-hairpin loop mimetics of formulaeIa and Ib. For the deprotection, i.e. cleaving off of the Fmoc group,20% piperidine in DMF or 2% DBU/2% piperidine in DMF can be used.

[0750] The quantity of the reactant, i.e. of the amino acid derivative,is usually 1 to 20 equivalents based on the milliequivalents per gram(meq/g) loading of the functionalized solid support (typically 0.1 to2.85 meq/g for polystyrene resins) originally weighed into the reactiontube. Additional equivalents of reactants can be used if required todrive the reaction to completion in a reasonable time. The reactiontubes, in combination with the holder block and the manifold, arereinserted into the reservoir block and the apparatus is fastenedtogether. Gas flow through the manifold is initiated to provide acontrolled environment, for example, nitrogen, argon, air and the like.The gas flow may also be heated or chilled prior to flow through themanifold. Heating or cooling of the reaction wells is achieved byheating the reaction block or cooling externally with isopropanol/dryice and the like to bring about the desired synthetic reactions.Agitation is achieved by shaking or magnetic stirring (within thereaction tube). The preferred workstations (without, however, beinglimited thereto) are Labsource's Combi-chem station and MultiSynTech's-Syro synthesizer.

[0751] Amide bond formation requires the activation of the α-carboxylgroup for the acylation step. When this activation is being carried outby means of the commonly used carbodiimides such asdicyclohexylcarbodiimide (ICC, Sheehan & Hess, J. Am. Chem. Soc. 1955,77, 1067-1068) or diisopropylcarbodiimidc ([)IC, Sarantakis et alBiochem Biophys. Res. Commun.1976, 73, 336-342), the resultingdicyclohexylurea is insoluble and, respectively, diisopropylurea issoluble in the solvents generally used. In a variation of thecarbodiitnide method I-hydroxybenzotriazole (HOBt, König & Geiger, Chem.Ber 1970, 103, 788-798) is included as an additive to the couplingmixture. HOBt prevents dehydration, suppresses racemization of theactivated amino acids and acts as a catalyst to improve the sluggishcoupling reactions. Certain phosphonium reagents have been used asdirect coupling reagents, such asbenzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate (BOP) (Castro et al., Tetrahedron Lett. 1975, 14,1219-1222; Synthesis, 1976, 751-752), orbenzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexaflurophoshate(Py-BOP, Coste et al., Tetrahedron Lett. 1990, 31, 205-208), or2-(1H-benzotriazol-1-yl-)1,1,3,3-tetramethyluronium terafluoroborate(TBTU), or hexafluorophosphate (HBTU, Knorr et al., Tetrahedron Lett.1989, 30, 1927-1930); these phosphonium reagents are also suitable forin situ formation of HOBt esters with the protected amino acidderivatives. More recently diphenoxyphosphoryl azide (DPPA) orO-(7-aza-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (TATU) orQ-7-aza-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU)/7-aza-1-hydroxy benzotriazole (HOAt, Carpinoet al., Tetrahedron Lett. 1994, 35, 2279-2281) have also been used ascoupling reagents.

[0752] Due to the fact that near-quantitative coupling reactions areessential it is desirable to have experimental evidence for completionof the reactions. The ninhydrin test raiser et al., Anal. Biochemistry1970, 34, 595), where a positive colorimetric response to an aliquot ofresin- bound peptide indicates qualitatively the presence of the primaryamine, can easily and quickly be performed after each coupling step.Fmoc chemistry allows the spectrophotometric detection of the Fmocchromophore when it is released with the base (Meienhofer et al., Int.J. Peptide Protein Res. 1979, 13, 3542).

[0753] The resin-bound intermediate within each reaction tube is washedfree of excess of retained reagents, of solvents, and of by-products byrepetitive exposure to pure solvent(s) by one of the two followingmethods:

[0754] 1) The reaction wells are filled with solvent (preferably 5 ml),the reaction tubes, in combination with the holder block and manifold,are immersed and agitated for 5 to 300 minutes, preferably 15 minutes,and drained by gravity followed by gas pressure applied through themanifold inlet (while closing the outlet) to expel the solvent;

[0755] 2) The manifold is removed from the holder block, aliquots ofsolvent (preferably 5 ml) are dispensed through the top of the reactiontubes and drained by gravity through a filter into a receiving vesselsuch as a test tube or vial.

[0756] Both of the above washing procedures are repeated up to about 50times (preferably about 10 times), monitoring the efficiency of reagent,solvent, and byproduct removal by methods such as TLC, GC, or inspectionof the washings.

[0757] The above described procedure of reacting the resin-boundcompound with reagents within the reaction wells followed by removal ofexcess reagents, by-products, and solvents is repeated with eachsuccessive transformation until the final Tesin-bound fully protectedlinear peptide has been obtained

[0758] Before this fully protected linear peptide is detached from thesolid support, it is possible, if desired, to selectively deprotect oneor several protected functional group(s) present in the molecule and toappropriately substitute the reactive group(s) thus liberated. To thiseffect, the functional group(s) in question must initially be protectedby a protecting group which can be selectively removed without affectingthe remaining protecting groups present. Alloc (allyloxycarbonyl) is anexample for such a protecting group for amino which can be selectivelyremoved, e.g. by means of Pd° and phenylsilane in CH₂Cl₂, withoutaffecting the remaining protecting groups, such as Fmoc, present in themolecule. The reactive group thus liberated can then be treated with anagent suitable for introducing the desired substituent. Thus, forexample, an amino group can be acylated by means of an acylating agentcorresponding to the acyl substituent to be introduced.

[0759] Detachment of the fully protected linear peptide from the solidsupport is achieved by immersion of the reaction tubes, in combinationwith the holder block and manifold, in reaction wells containing asolution of the cleavage reagent (preferably 3 to 5 ml). Gas flow,temperature control, agitation, and reaction monitoring are implementedas described above and as desired to effect the detachment reaction. Thereaction tubes, in combination with the holder block and manifold, aredisassembled from the reservoir block and raised above the solutionlevel but below the upper lip of the reaction wells, and gas pressure isapplied through the manifold inlet (while closing the outlet) toefficiently expel the final product solution into the reservoir wells.The resin remaining in the reaction tubes is then washed 2 to 5 times asabove with 3 to 5 ml of an appropriate solvent to extract (wash out) asmuch of the detached product as possible. The product solutions thusobtained are combined, taking care to avoid cross-mixing. The individualsolutions/extracts are then manipulated as needed to isolate the finalcompounds. Typical manipulations include, but are not limited to,evaporation, concentration, liquid/liquid extraction, acidification,basification, neutralization or additional reactions in solution.

[0760] The solutions containing fully protected linear peptidederivatives which have been cleaved off from the solid support andneutralized with a base, are evaporated. Cyclization is then effected insolution using solvents such as DCM, DMF, dioxane, ThF and the like.Various coupling reagents which were mentioned earlier can be used forthe cyclization. The duration of the cyclization is about 6-48 hours,preferably about 24 hours. The progress of the reaction is followed,e.g. by RP-HPLC (Reverse Phase High Performance Liquid Chromatography).Then the solvent is removed by evaporation, the fully protected cyclicpeptide derivative is dissolved in a solvent which is not miscible withwater, such as DCM, and the solution is extracted with water or amixture of water-miscible solvents, in order to remove any excess of thecoupling reagent.

[0761] Before removing the protecting groups from the fully protectedcyclic peptide, it is possible, if desired, to form an interstrandlinkage between side-chains of appropriate amino acid residues atopposite positions of the β-strand region; and/or to connect twobuilding blocks of the type of formula Ia via a bridge -G1-L-G2- to givea dimeric structure of the type of formula Ib.

[0762] Interstrand linkages and their formation have been discussedabove, in connection with the explanations made regarding groups of thetype H which can, for example, be disulfide bridges formed by cysteinesand homocysteines at opposite positions of the β-strand, or glutamic andaspartic acid residues linking ornithines and, respectively, lysineslocated at opposite β-strand positions by amide bond formation. Theformation of such interstrand linkages can be effected by methods wellknown in the art.

[0763] Interstrand linkages and their formation have been discussedabove, in connection with the explanations made regarding groups of thetype H which can, for example, be disulfide bridges formed by cysteinesand homocysteines at opposite positions of the N-strand, or glutamic andaspartic acid residues linking ornithines and, respectively, lysineslocated at opposite β-strand positions by amide bond formation. Theformation of such interstrand linkages can be effected by methods wellknown in the art.

[0764] For building up a bridge -G1-L-G2- to give a dimeric structure,methods well known in the art can be used, too. Thus, for example, afully side-chain protected β-hairpin peptidomimetic carrying a group G1or G2 containing an appropriately protected alcohol group (e.g. astert.-butyldiphenylsilyl protected), thiol group (e.g. asacetamidomethyl protected) or amino group (NR³⁴; e.g. asallyloxycarbonyl protected) can selectively be deprotected employingmethods well known by the skilled in the art and reacted with suitablyactivated linker (L) precursors; e.g:

[0765] for L1 the corresponding building block isBr(Cl,I)(CH₂)_(p)CHR⁶¹[X(CH₂)_(p)CHR⁶¹]_(o)OH: the resulting alcohol canbe transformed into the corresponding bromide (chloride or iodide) bymethods well known to those skilled in the art (e.g. P(Ph)₃, CBr₄) andcombined with a second β-hairpin mimetic carrying a group G1 or G2containing an alcohol, thiol or amine group. The dimeric fullyside-chain protected molecule can be fully deprotected and purified bypreparative HPLC chromatography as described in procedure 1,hereinbelow.

[0766] for L2 the corresponding building block is

[0767] ClOC(CH₂)_(p)CHR⁶¹[X(CH₂)_(p)CHR⁶¹]_(o)COOAllyl: the resultingester can be transformed into the corresponding acid by methods wellknown in the art and combined with a second β-hairpin mimetic carrying agroup G1 or G2 containing an alcohol, thiol or amine group. The dimericfully side-chain protected molecule can be fully deprotected andpurified by preparative HPLC chromatography as described in procedure 1,hereinbelow.

[0768] For L3 the corresponding building block is

[0769] O═C═N(CH₂)_(p)CHR⁶¹[X(CH₂)_(p)CHR⁶¹]_(o)NR³⁴Alloc: the resultingAlloc-protected amine can be deprotected and transformed into thecorresponding isocyanate by methods familiar to those skilled in the art(e.g. triphosgene) and combined with a second β-hairpin mimetic carryinga group G1 or G2 containing an alcohol, thiol or amine group. Thedimeric fully side-chain protected molecule can be fully deprotected andpurified by preparative HPLC chromatography as described in procedure 1,hereinbelow.

[0770] For L7 the corresponding building block isBr(Cl,I)(CH₂)_(o)CHR⁶¹Y(CH₂)_(o)CHR⁶¹OH: the resulting alcohol can betransformed into the corresponding bromide (chloride or iodide) bymethods well known in the art (e.g. P(Ph)₃, CBr₄) and combined with asecond β-hairpin mimetic carrying a group G1 or G2 containing analcohol, thiol or amine group. The dimeric fully side-hain protectedmolecule can be deprotected and purified by preparative HPLCchromatography as described in procedure 1, hereinbelow.

[0771] For L8 the corresponding building block isClOC(CH₂)_(o)CHR⁶¹Y(CH₂)_(o)CHR⁶¹COOAllyl: the resulting ester can betransformed into the corresponding acid by methods well known to thoseskilled in the art and combined with a second β-hairpin mimetic carryinga group G1 or G2 containing an alcohol, thiol or amine group. Thedimeric fully side-chain protected molecule can be deprotected andpurified by preparative HPLC chromatography as described in procedure 1,hereinbelow.

[0772] For L9 the corresponding building block isO═C═N(CH₂)_(o)CHR⁶¹Y(CH₂)_(o)CHR⁶¹NR³⁴Alloc: the resultingAlloc-protected amine can be deprotected and transformed into thecorresponding isocyanate by methods well known in the art (e.g.triphosgene) and combined with a second β-hairpin mimetic carrying agroup G1 or G2 containing an alcohol, thiol or amine group. The dimericfully side-chain protected molecule can be deprotected and purified bypreparative HPLC chromatography as described in procedure 1,hereinbelow.

[0773] For L13 the corresponding building block isClOC(CH₂)_(p)CHR⁶¹[X(CH₂)_(p)CHR⁶¹]_(o)NR³⁴Alloc: the resultingAlloc-protected amine can be deprotected by methods readily available tothose skilled in the art and combined with a second β-hairpin mimeticcarrying a group G1 or G2 containing a carboxylic acid group. Thedimeric fully side-chain protected molecule can be deprotected andpurified by preparative HPLC chromatography as described in procedure 1,hereinbelow.

[0774] For L14 the corresponding building block isClOC(CH₂)_(o)CHR⁶¹Y(CH₂)_(o)CHR⁶¹N³⁴Alloc: the resulting Alloc-protectedamine can be deprotected by conventional methods and combined with asecond β-hairpin mimetic carrying a group G1 or G2 containing acarboxylic acid group. The dimeric fully side-chain protected moleculecan be deprotected and purified by preparative HPLC chromatography asdescribed in procedure 1, hereinbelow.

[0775] Alternatively, a fully side-chain protected β-hairpinpeptidomimetic carrying a group G1 or G2 containing an appropriatelyprotected thiol group (e.g. as acetamidomethyl protected) canselectively be deprotected employing methods well known to those skilledin the art and reacted with a second β-hairpin peptidomimetic carrying agroup G1 or G2 containing a thiol group forming a disulfide bond byoxidation (air or iodine). The dimeric molecule can subsequentlybe-fully deprotected and purified by preparative HPLC chromatography asdescribed in procedure 1, hereinbelow.

[0776] Finally, a fully side-chain protected β-hairpin peptidomimeticcarrying a group G1 or G2 containing an appropriately protectedcarboxylic acid group (e.g. allyl ester), can selectively be deprotectedemploying methods well known in the art and reacted with a suitablyactivated linker (L) precursor; e.g:

[0777] For L4 the corresponding building block isHO(CH₂)_(p)CHR⁶¹[X(CH₂)_(p)CHR⁶¹]_(o)OAlloc: the resultingAlloc-protected alcohol can be deprotected by methods well known tothose skilled in the art and combined with a second β-hairpin mimeticcarrying a group G1 or G2 containing a carboxylic acid group. Thedimeric fully side-chain protected molecule can be deprotected andpurified by preparative HPLC chromatography as described in procedure 1,hereinbelow.

[0778] For L5 the corresponding building block isHS(CH₂)_(p)CHR⁶¹[X(CH₂)_(p)CHR⁶¹]_(o)SAlloc: the resultingAlloc-protected thiol can be deprotected by methods well known in theart and combined with a second β-hairpin mimetic carrying a group G1 orG2 containing a carboxylic acid group. The dimeric fully side-chainprotected molecule can be deprotected and purified by preparative HPLCchromatography as described in procedure 1, hereinbelow.

[0779] For L6 the corresponding building block isH(CH₂)_(p)CHR⁶¹[X(CH₂)_(p)CHR⁶¹]_(o)NR³⁴Alloc: the resultingAlloc-protected amine can be deprotected by methods familiar to thoseskilled in the art and combined with a second β-hairpin mimetic carryinga group G1 or G2 containing a carboxylic acid group. The dimeric fullyside-chain protected molecule can be deprotected and purified bypreparative HPLC chromatography as described in procedure 1,hereinbelow.

[0780] For L10 the corresponding building block isHO(CH₂)_(o)CHR⁶¹Y(CH₂)CHR⁶¹OAlloc: the resulting Alloc-protected alcoholcan be deprotected by methods well known to those skilled in the art andcombined with a second β-hairpin mimetic carrying a group G1 or G2containing a carboxylic acid group. The dimeric fully side-chainprotected molecule can be deprotected and purified by preparative HPLCchromatography as described in procedure 1, hereinbelow.

[0781] For L11 the corresponding building block isHS(CH₂)_(o)CHR⁶¹Y(CH₂)_(o)CHR⁶¹SAlloc: the resulting Alloc-protectedthiol can be deprotected by methods well known in the art and combinedwith a second β-hairpin mimetic carrying a group G1 or G2 containing acarboxylic acid group. The dimeric fully side-chain protected moleculecan be deprotected and purified by preparative TPLC chromatography asdescribed in procedure 1, hereinbelow.

[0782] For L12 the corresponding building block is

[0783] HNR³⁴(CH₂)_(o)CHR⁶¹Y(CH₂)_(o)CHR⁶¹NR³⁴Alloc: the resultingAlloc-protected amine can be deprotected by methods well known to thoseskilled in the art and combined with a second β-hairpin mimetic carryinga group G1 or G2 containing a carboxylic acid group. The dimeric fullyside-chain protected molecule can be deprotected and purified bypreparative HPLC chromatography as described in procedure 1,hereinbelow.—

[0784] For L15 the corresponding building block is

[0785] HNR³⁴(CH₂)_(p)CHR⁶¹[X(CH₂)_(p)CHR⁶¹]_(o)COOAllyl: the resultingAllylester can be deprotected by conventional methods and combined witha second β-hairpin mimetic carrying a group G1 or G2 containing analcohol group, a thiol group or an amino (NR³⁴) group. The dimeric fullyside-chain protected molecule can be deprotected and purified bypreparative HPLC chromatography as described in procedure 1,hereinbelow.

[0786] For L16 the corresponding building block isHNR³⁴(CH₂)_(o)CHR⁶¹Y(CH₂)_(o)CHR⁶¹COOAllyl: the resulting Allylester canbe deprotected by methods well known to those skilled in the art andcombined with a second β-hairpin mimetic carrying a group G1 or G2containing an alcohol group, a thiol group or an amino (NR³⁴) group. Thedimeric fully side-chain protected molecule can be deprotected andpurified by preparative HPLC chromatography as described in procedure I,hereinbelow.

[0787] Finally, the fully protected peptide derivative of type Ia or Ibis treated with 95% TFA, 2.5% H₂O, 2.5% TIS or another combination ofscavengers for effecting the cleavage of protecting groups. The cleavagereaction time is commonly 30 minutes to 12 hours, preferably about 2hours. Thereafter most of the TFA is evaporated and the product isprecipitated with ether/hexane (1:1) or other solvents which aresuitable therefor. After careful removal of the solvent, the cyclicpeptide derivative obtained as end-product can be isolated. Depending onits purity, this peptide derivative can be used directly for biologicalassays, or it has to be further purified, for example by preparativeHPLC.

[0788] As mentioned earlier, it is thereafter possible, if desired, toconvert a fully deprotected product thus obtained into apharmaceutically acceptable salt or to convert a pharmaceuticallyacceptable, or unacceptable, salt thus obtained into the correspondingfree compound of formula Ia and Ib or into a different, pharmaceuticallyacceptable, salt. Any of these operations can be carried out by methodswell known in the art.

[0789] The starting materials used in the process of the invention,pre-starting materials therefor, and the preparation of these startingand pre-starting materials will now be discussed in detail.

[0790] Building blocks of type A can be synthesized according to theliterature methods described below. The corresponding amino acids havebeen described either as unprotected or as Boc- or Fmoc-protectedracemates, (D) or (L)-isomers. It will be appreciated that unprotectedamino acid building blocks can be easily transformed into thecorresponding Fmoc-protected amino acid building blocks required for thepresent invention by standard protecting group manipulations. Reviewsdescribing general methods for the synthesis of -amino acids include: RDuthaler, Tetrahedron (Report) 1994, 349, 1540-1650; R. M. Williams,“Synthesis of optically active α-amino acids”, Tetrahedron OrganicChemistry Series, Vol.7, J. E. Baldwin, P. D. Magnus (Eds.), PergamonPress., Oxford 1989. An especially useful method for the synthesis ofoptically active α-amino acids relevant for this invention includeskinetic resolution using hydrolytic enzymes (M. A. Verhovskaya, I. A.Yamskov, Russian Chem. Rev. 1991, 60, 1163-1179; R. M. Williams,“Synthesis of optically active α-amino acids”, Tetrahedron OrganicChemistry Series, Vol.7, J. E. Baldwin, P. D. Magnus (Eds.), PergamonPress., Oxford 1989, Chapter 7, p.257-279). Hydrolytic enzymes involvehydrolysis of amides and nitrites by aminopeptidases or nitrilases,cleavage of N-acyl groups by acylases, and ester hydrolysis by lipasesor proteases. It is well documented that certain enzymes will leadspecifically to pure (L)-enantiomers whereas others yield thecorresponding (D)-enantiomers (e.g.: R Duthaler, Tetrahedron Report1994, 349, 1540-1650; R. M. Williams, “Synthesis of optically activeα-amino acids”, Tetrahedron Organic Chemistry Series, Vol.7, J. E.Baldwin, P. D. Magnus (Eds.), Pergamon Press., Oxford 1989).

[0791] A1: See D. Ben-Ishai, Tetrahedron 1977, 33, 881-883; K. Sato, A.P. Kozikowski, Tetrahedron Lett. 1989, 30, 4073-4076; J. E. Baldwin, C.N. Farthing, A. T. Russell, C. J. Schofield, A. C. Spirey, TetrahedronLett. 1996, 37, 3761-3767; J. E. Baldwin, R. M. Adlington, N. G.Robinson, J. Chem. Soc. Chem. Commun. 1987, 153-157; P. Wipf, Y. Uto,Tetrahedron Lett. 1999, 40, 5165-5170; J. E. Baldwin, R. M. Adlington,A. O'Neil, A. C. Spirey, J. B. Sweeney, J. Chem. Soc. Chem. Commun.1989, 1852-1854 (for R¹═H, R²═H); T. Hiyama, Bull. Chem. Soc. Jpn. 1974,47, 2909-2910; T. Wakamiya, K. Shimbo, T. Shiba, K. Nakajima, M. Neya,K. Okawa, Bull. Chem. Soc. Jpn. 1982, 55, 3878-3881; I. Shima, N.Shimazaki, K. Imai, K. Hemmi, M. Hashimoto, Chem. Pharm. Bull. 1990, 38,564-566; H. Han, J. Yoon, K. D. Janda, J. Org. Chem. 1998, 63, 2045-2048(R¹═H, R²=Me); J. Legters, G. H. Willems, L. Thijs, B. Zwannenburg,Recl. Trav. Chim. Pays-Bas 1992, 111, 59-68 (R¹═H, R²=hexyl); J.Legters, L. Thijs, B. Zwannenburg, Recl. Trav. Chim. Pays-Bas 1992, 111,16-21; G. A. Molander, P. J. Stengel, J. Org. Chem. 1995, 21, 6660-6661(R¹═H, R²=Ph); I. Funaki, L. Thijs, B. Zwannenburg, Tetrahedron 1996,52, 9909-9924 (R¹═H, R²=Bn); A S. Pepito, D. C. Dittmer, J. Org. Chem.1997, 62, 7920-7925; (R¹═H, R²═CH₂OH); M. Fgli, A. S. Dreiding, Helv.Chim. Acta 1986, 69, 1442-1460 (R²═CH(OH)CH₂OH); M. Carduccu, S.Fioravanti, M. A. Loreto, L. Pellacani, P. A. Tardella, TetrahedronLett. 1996, 37, 3777-3778; F. J. Lakner, L. P. Hager, Tetrahedron:Asymmetry 1997, 21, 3547-3550 (R¹=Me, R²═H, Me); G. A. Molander, P. J.Stengel, Tetrahedron 1997, 26, 8887-8912; M. A. Loreto, F. Pompei, P. A.Tardella, D. Tofani, Tetrahedron 1997, 53, 15853-15858 (R¹=Me,R²═CH₂SiMe₃); H. Shao, J. K. Rueter, M. Goodman, J. Org. Chem. 1998, 63,5240-5244 (R¹=Me, R²=Me).

[0792] A2: See A. Rao, M. K.Gwajr, V. Vivarr, Tetrahedron: Asymmetry1992, 3, 859-862; 1 L. Johnson, G. Rayakumar, K.-L. Yu, R. K. Misra, J.Med. Chem. 1986, 29, 2104-2107 (R¹═H, R²═H); J. E. Baldwin, R. M.Adlington, R. H. Jones, C. J. Schofield, C. Zarcostas, J. Chem. Soc.Chem. Commun. 1985, 196-196; J. E. Baldwin, R. M. Adlington, R. H.Jones, C. J. Schofield, C. Zarcostas, Tetrahedron 1986, 42, 4879-4888(R¹═H, R²═CH₂OH, CH₂CHO, CH₂CH₂COOH, CH₂CH₂OH); A. P. Kozikowski, W.Tueckmantel, I. J. Reynolds, J. T. Wroblewski, J. Med. Chem. 1990, 33,1561-1571; A. P. Kozikowski, W. Tueclanantel, Y. Liao, H. Manev, S.Ikonomovic J. T. Wroblenski, J. Med. Chem. 1993, 36, 2706-2708 (R¹═H,R²═CH₂OH, CHCONH₂, CONHCH₂COOH, COOtBu); D. Seebach, T. Vettiger, H.-M.Müller, D. Plattner, W. Petter, Liebigs Ann. Chem. 1990, 687-695(R¹=ArylCH(OH), R²═H); D. Seebach, E. Dziadulewicz, L. Behrendt, S.Cantoreggi, R. Fitzi, Liebigs Ann. Chem. 1989, 1215-1232 (R¹=Me, Et,R²═H).

[0793] A3: See A. P. Kozikowski, Y. Liao, W. Tueckmantel, S. Wang, S.Pshsenichkin, Bioorg. Med. Chem. Lett. 1996, 6, 2559-2564 (R¹═H;R²═CHCHO, CH₂OH, CH₂CH₂OH, CH₂COOH, COOH); Isono, J. Am. Chem. Soc,1969, 91, 7490 (R¹═H; R²=Et); P. J. Blythin, M. J. Green, M. J. Mary, H.Shue, J. Org. Chem. 1994, 59, 6098-6100; S. Hanessian, N. Bernstein,R.-Y. Yang, R. Maquire, Bioorg. Chem. Lett. 1994, 9, 1437-1442 (R¹═H;R²=Ph).

[0794] A4: See G. Emmer, Tetrahedron 1992, 48, 7165-7172; M. P. Meyer,P. L. Feldman, H. Rapoport, J. Org. Chem. 1985, 50, 5223-5230 (R¹═H;R²═H); A. J. Bose, M. S. Manhas, J. E. Vincent, I. F. Fernandez, J. Org.Chem 1982, 47, 4075-4081 (R¹═H; R²═NHCOCH₂OPh); D. L. Boger, J. B.Meyers, J. Org. Chem. 1991, 56, 5385-5390 (R¹═H; R²═NHCOCH₂Ph); K.-D.Kampe, Tetrahedron Lett. 1969, 117-120 (R¹═CH₂OH; R²=Ph); M. D. Andrews,M. G. Maloney, K. L. Owen, J. Chem. Soc. Perkin Trans.1, 1996, 227-228(R¹═CH₂OH; R²═H).

[0795] A5: See C. Bisang, C. Weber, J. Inglis, C. A. Schiffer, W. F. vanGunsteren, J. A. Robinson J. Am. Chem. Soc. 1995, 117, 7904 (R¹═CH₃;R²═H); S. Takano, M. Morija, Y. Iwabuki, K. Ogasawara, Tetrahedron Lett.1989, 30, 3805-3806 (R¹═H; R²═COOH); M. D. Bachi, R. Breiman, H.Meshulam, J. Org. Chem. 1983, 48, 1439-1444 (R¹═H; R²═CH(Et)COOH); D. S.Kemp, T. P. Curran, Tetrahedron Lett. 1988, 29, 4931-4934; D. S. Kemp,T. P. Curran, W. M. Davies, J. Org. Chem. 1991, 56, 6672-6682 (R¹═H;R²═CH₂OH); F. Manfre, J.-M. Kern, J.-F. Biellmann, J. Org. Chem. 1992,57, 2060-2065 (R¹═H; R²═H, CH═CH₂, CCH); B. W. Bycroft, S. R. Chabra, J.Chem. Soc. Chem. Commun. 1989, 423-425 (R¹═H; R²═CH₂COOtBu; Y. Xu, J.Choi, M. I. Calaza, S. Turner, H. Rapoport, J. Org. Chem. 1999, 64,4069-4078 (R¹═H; R²=3-pyridyl); E. M. Khalil, W. J. Ojala, A. Pradham,V. D. Nair, W. B. Gleason, J. Med. Chem 1999, 42, 628-637; E. M. Khalil,N. L. Subasinghe, R. L. Johnson, Tetrahedron Lett. 1996, 37, 3441-3444(R¹=allyl; R²═H); A. DeNicola, J.-L. Luche, Tetrahedron Lett. 1992, 33,6461-6464; S. Thaisrivongs, D. T. Pals, J. A. Lawson, S. Turner, D. W.Harris, J. Med. Chem. 1987, 30, 536-541; E. M. Khalil, N. L. Subasinghe,R. L. Johnson, Tetrahedron Lett. 1996, 37, 3441-3444; A. Lewis, J.Wilkie, T. J. Rutherford, D. Gani, J. Chem. Soc. Perkin Trans.1, 1998,3777-3794 (R¹=Me; R²═H); A. Lewis, J. Wilkie, T. J. Rutherford, D. Gani,J. Chem. Soc. Perkin Trans.1, 1998, 3777-3794 (R¹═CH₂COOMe; R²═H); N. L.Subasinghe, E. M. Khalil, R. L. Johnson, Tetrahedron Lett. 1997, 38,1317-1320 (R¹═CH₂CHO; R²═H); D. J. Witter, S. J. Famiglietti, J. C.Gambier, A. L. Castelhano, Bioorg. Med. Chem. Lett. 1998, 8, 3137-3142;E. H. Khalil, W. H. Ojada, A. Pradham, V. D. Nair, W. B. Gleason, J.Med. Chem. 1999, 42, 628-637 (R¹═CH₂CH₂CHO; R²═H).

[0796] A6: See DeNardo, Farmaco Ed. Sci. 1977, 32, 522-529 (R¹═H; R³═H);P. J. T. Floris, N. Terhuis, H. Hiemstra, N. W. Speckamp, Tetrahedron,1993, 49, 8605-8628; S. Kanemasa, N. Tomoshige, O. Tsuge, Bull. Chem.Soc. Jpn. 1989, 62, 3944-3949 (R¹═H; R³═H); Sucrow, Chem. Ber. 1979,112, 1719.

[0797] A7: See Fichter, J. Prakt. Chem. 1906, 74, 310 (R¹=Me; R⁴=Ph).

[0798] A8: See L. Lapantsanis, G. Milias, K. Froussios, M. Kolovos,Synthesis 1983, 641-673; H. Nedev, H. Naharisoa, Tetrahedron Lett. 1993,34, 4201-4204; D. Y. Jackson, C. Quan, D. R Artis, T. Rawson, B.Blackburn, J. Med. Chem. 1997, 40, 3359-3368; D. Konopinska, H.Bartosz-Bechowski, G. Rosinski, W. Sobotka, Bull. Pol. Acad. Sci. Chem.1993, 41, 2740; J. Hondrelis, G. Lonergan, S. Voliotis, J. Matsukas,Tetrahedron 1990, 46, 565-576; T. Nakamura, H. Matsuyama, H. Kanigata,M. Iyoda, J. Org. Chem. 1992, 57, 3783-3789; C. E. O'Connell, K.Ackermanr, C. A. Rowell, A. Garcia, M. D. Lewis, C. E. Schwartz, Bioorg.Med. Chem. Lett. 1999, 9, 2095-2100; G. Lowe, T. Vilaivan, J. Chem. Soc.Perkin Trans. 1997, 547-554; B. Bellier, 1. McCourt-Tranchepain, B.Ducos, S. Danascimenta, H. Mundal, J. Med. Chem. 1997, 40, 3947-3956; M.Peterson, R. Vince J. Med. Chem. 1991, 34, 2787-2797; E. M. Smith, G. F.Swiss, B. R. Neustadt, E. H. Gold, J. A. Sommer, J. Med. Chem. 1988, 31,875-885; E. Rubini, C. Gilon, Z. Selinger, M. Chorev, Tetrahedron 1986,42, 6039-6045 (R¹═H; R⁵═OH); C. R. Noe, M. Knollmueller, H. Voellenkle,M. Noe-Letschnig, A. Weigand, J. Mülh, Pharmazie, 1996, 51, 800-804(R¹═CH₃; R⁵═OH); J. Kitchin, R C. Berthel, N. Canmmack, S. Dolan, D. N.Evans, J. Med. Chem. 1994, 37, 3703-3716; D. Y. Jackson, C. Quan, D. R.Artis, T. Rawson, B. Blackburn, J. Med. Chem. 1997, 40, 3359-3368 (R¹═H;R⁵=OBn); J. E. Baldwin, A. R. Field, C. C. Lawrence, K. D. Merritt, C.J. Schofield, Tetrahedron Lett. 1993, 34, 7489-7492; K. Hashimoto, Y.Shima, H. Shirahama, Heterocycles 1996, 42, 489-492 (R¹═H; R⁵=OTs); T.R. Webb, C. Eigenbrot, J. Org. Chem. 1991, 56, 3009-3016; D. C.Cafferty, C. A. Slate, B. M. Nakhle, H. D. Graham, T. L. Anstell,Tetrahedron 1995, 51, 9859-9872 (R¹═H; R⁵═NH₂); T. R. Webb, C.Eigenbrot, J. Org. Chem. 1991, 56, 3009-3016 (R¹═H; R⁵═CH₂NH₂); J. K.Thottathil, J. L. Moniot, Tetrahedron Lett. 1986, 27, 151-154 (R¹═H;R⁵=Ph); K. Plucinska, T. Kataoka, M. Yodo, W. Cody, J. Med. Chem. 1993,36, 1902-1913 (R¹═H; R⁵=SBn); J. Krapcho, C. Turk, D. W. Cushman, J. RPowell, J. Med. Chem. 1988, 31, 1148-1160 (R¹═H; R⁵=SPh); A. J.Verbiscar, B. Witkop, J. Org. Chem. 1970, 35, 1924-1927 (R¹═H;R⁵═SCH₂(4-OMe)C₆H₄); S. I. Klein, J. M. Denner, B. F. Molino, C.Gardner, R. D'Alisa, Bioorg. Med. Chem. Lett. 1996, 6, 2225-2230 (R¹═H;R⁵═O(CH₂)₃Ph); R. Zhang, F. Brownewell, J. S. Madalengoita, TetrahedronLett. 1999, 40, 2707-2710 (R¹═H; R⁵═CH₂COOBn).

[0799] A9: See Blake, J. Am. Chem. Soc. 1964, 86, 5293-5297; J. Cooper,R. T. Gallagher, D. T. Knight, J. Chem. Soc. Chem. Perkin Trans.1, 1993,1313-1318; D. W. Knight, A. W. Sibley, J. Chem. Soc. Perkin Trans.1,1997, 2179, 2188 (R¹═H; R⁶═H); Blake, J. Am. Chem. Soc. 1964, 86,5293-5297; Y. Yamada, T. Ishii, M. Kimura, K. Hosaka, Tetrahedron Lett.1981, 1353-1354 (R¹═H; R⁶═OH); Y. Umio, Yakugahu Zasshi, 1958, 78, 727(R¹═H; R⁶=iPr); Miyamoto, Yahugaku Zasshi, 1957, 77, 580-584; Tanaka,Proc. Jpn. Acad. 1957, 33, 47-50 (R¹═H; R⁶═CH(CH₃)CH₂N(CH₃)₂); L. E.Overman, B. N. Rodgers, J. E. Tellew, W. C. Trenkle, J. Am. Chem. Soc.1997, 119, 7159-7160 (R¹═H; R⁶=allyl); Obki, Chem. Pharm. Bull. 1976,24, 1362-1369 (R¹═CH₃; R⁶═H).

[0800] A10: See J. Mulzer, A. Meier, J. Buschmann, P. Luger, Synthesis1996, 123-132 (R¹═H; R⁷═CH═CH₂); J. Cooper, P. T. Gallagher, D. W.Knight, J. Chem. Soc. Chem. Commun. 1988, 509-510; E. Götschi, C. Jenny,P. Reindl, F. Ricklin, Helv. Chim. Acta 1996, 79, 2219-2234 (R¹═H;R⁷═OH); N. K Sasald, R Pauli, C. Fontaine, A. Chiaroni, C. Riche, P.Potier, Tetrahedron Lett. 1994, 35, 241-244 (R¹═H; R⁷═COOH); R. Cotton,A. N.C. Johnstone, M. North, Tetrahedron 1995, 51, 8525-8544 (R¹═H;R⁷═COOMe); J. S. Sabol, G. A. Flynn, D. Friedrich, E. W. Huber,Tetrahedron Lett. 1997, 38, 3687-3690 (R¹═H; R⁷═CONH₂); P. P. Waid, G.A. Flynn, E. W. Huber, J. S. Sabol, Tetrahedron Lett. 1996, 37,4091-4094 (R¹═H; R¹=(4-BnO)C₆H₄); N. A. Sasaki, R. Pauli, P. Potier,Tetrahedron Lett. 1994, 35, 237-240 (R¹═H; R⁷═SO₂Ph); R. J. Heffner, J.Jiang, M. Jouillié, J. Am. Chem. Soc. 1992, 114, 10181-10189; U.Schmidt, H. Griesser, A. Lieberknecht, J. Häusler, Angew. Chem. 1981,93, 272-273 (R¹═H; R⁷=OAryl); H. Mosberg, A. L. Lomize, C. Wang, H.Kroona, D. L. Heyl, J. Med. Chem. 1994, 37, 4371-4383 (R¹═H;R⁷=4-OHC₆H₄); S. A. Kolodziej, G. V. Nikiforovich, R. Sceean, M.-F.Lignon, J. Martinez, G. R. Marshall, J. Med. Chem. 1995, 38, 137-149(R¹═H; R⁷═SCH₂(4-Me)C₆H₄).

[0801] A11: See Kuhn, Osswald, Chem. Ber. 1956, 89, 1423-1434; Patchett,Witkop, J. Am. Chem. Soc. 1957, 79, 185-189; Benz, Helv. Chim. Acta1974, 57, 2459-2475; P. Wessig, Synlett, 1999, 9, 1465-1467; E. M. Smit,G. F. Swiss, B. R. Neustadt, E. H. Gold, J. A. Sommer, J. Med. Chem.1988, 31, 875-885; J. Krapcho, C. Turk, D. W. Cushman, J. R. Powell, J.M. DeForrest, J. Med. Chem. 1988, 31, 1148 (R¹═H; R⁶═H); D. BenIshai, S.Hirsh, Tetrahedron 1988, 44, 5441-5450 (R¹═H; R⁶═CH₃); M. W. Holladay,C. W. Lin, C. S. Garvey, D. G. Witte, J. Med. Chem. 1991, 34, 455-457(R¹═H; R⁶=allyl); P. Barralough, P. Hudhonmme, C. A. Spray, D. W. Young,Tetrahedron 1995, 51, 4195-4212 (R¹═H; R⁶=Et); J. E. Baldwin, M. Rudolf,Tetrahedron Lett. 1994, 35, 6163-6166; J. E. Baldwin, S. J. Bamford, A.M. Fryer, M. Rudolf, M. E. Wood, Tetrahedron 1997, 53, 5233-5254 (R¹═H;R⁶═CH₂COOtBu); P. Gill, W. D. Lubell, J. Org. Chem. 1995, 60, 2658-2659(R¹═H; R⁶═CH₃; Bn; allyl; —(CH₂COOMe); M. J. Blanco, F. J. Sardina, J.Org. Chem. 1998, 63, 3411-3466 (R¹═H; R⁶═OCH₂OMe).

[0802] A12: See Ahmed, Cheeseman, Tetrahedron 1977, 33, 2255-2257; J. S.New, J. P. Yevich, J. Heterocycl. Chem. 1984, 21, 1355-1360; R.Kikumoto, Y. Tarnao, K. Ohkubo, T. Tezuka, S. Tonomura, J. Med. Chem.1980, 23, 1293-1299; C. J. Blankley, J. S. Kaltenbronn, D. E. DeJohn, A.Werner, L. R. Bennett, J. Med. Chem. 1987, 30, 992-998; S. Klutcho, C.J. Blankley, R W. Fleming, J. M. Hinkley, R. E. Werner, J. Med. Chem.1986, 29, 1953-1961 (R¹═H; R⁸═H); L. J. Beeley, C. J. M. Rockwell,Tetrahedron Lett. 1990, 31, 417-420 (R¹═COOEt; R⁸═H).

[0803] A13: See G. Flouret, W. Brieher, T. Majewski, K. Mahan, J. Med.Chem. 1991, 43, 2089-2094; G. Galiendo, P. Grieco, E. Perissuti, V.Santagada, Farmaco, 1996, 51, 197-202; D. P. McComsey, M. J. Hawkins, P.Andrade-Gordon, M. F. Addo, B. E. Maryanoff, Bioorg. Med. Chem. Lett.1999, 9, 1423-1428; G. B. Jones, S. B. Heaton, B. J. Chapman, M. Guzel,Tetrahedron: Asymmetry 1997, 8, 3625-3636; M. Asami, H. Watanabe, K.Honda, S. Inoue, Tetrahedron: Asymmetry 1998, 9, 4165-4174; K. Gross, Y.M. Yun, P. Beak, J. Org. Chem. 1997, 62, 7679-7689 (R¹═H; R⁶═H; R⁸═H);K. Gross, Y. M. Yun, P. Beak, J. Org. Chem. 1997, 62, 7679-7689 (R¹═H;R⁶═H; R⁸=6-Cl); Ch. Noe, M. Knollmueller, C. Schoedl, M. L. Berger, Sci.Pharm. 1996, 64, 577-590; E. Reiman, W. Erdle, H. Unger, Pharmazie,1994, 54, 418-421 (R¹═H; R⁶═CH₂COOH; R⁸═H); V. Collot, M. Scbmitt, A. K.Marwah, B. Norerg, J.-J. Bourgignon, Tetrahedron Lett. 1997, 38,8033-8036 (R¹═H; R⁶=Ph; R⁸═H); L. V. Dunkerton, H. Chen, B. P.McKillican, Tetrahedron Lett. 1988, 29, 2539-2542 (R¹═C(CH₃)₂CH═CH₂;R⁶═H; R⁸═H); E. J. Corey, J. Am. Chem. Soc. 1970, 92, 2476-2488;Neunhoeffer, Lehmann, Chem. Ber. 1961, 94, 2960-2963 (R¹═CH₃; R⁶═H;R⁸═H).

[0804] A14: Amino acids of type A14 can be made according to Scheme 1.

[0805] A15: See D. S. Perlow, J. M. Erb, N. P. Gould, R. D. Tung, R. M.Freidinger, J. Org. Chem. 1992, 57, 4394-4400; D. Y. Jackson, C. Quan,D. R. Artis, T. Rawson, B. Blackburn, J. Med. Chem. 1997, 40, 3359-3368(R¹═H; R²═H); H. H. Wasserman, K. Rodrigues, K. Kucharozyl, TetrahedronLett. 1989, 30, 6077-6080 (R¹═H; R²═COOH).

[0806] A16: See Beyerman, Boekee, Recl. Trav. Chim. Pays-Bas, 1959, 78,648-653; M. E. Freed, A. R. Day, J. Org. Chem. 1960, 25, 2105-2107; D.R. Adams, P. D. Bailey, I. D. Collier, J. D. Heferman, S. Slokes, J.Chem. Soc. Chem. Commun. 1996, 349-350; J. E. Baldwin, R. M. Adlington,C. R. A. Godfrey, D. W. Collins, J. D. Vaughan, J. Chem. Soc. Chem.Commun. 1993, 1434-1435; Y. Matsuanura, Y. Takeshima, H. Ohita, Bull.Chem. Soc. Jpn. 1994, 67, 304-306 (R¹═H; R⁶═H); C. Herdeis, W. Engel,Arch. Pharm. 1991, 324, 670 (R¹═COOMe; R⁶═CH₃).

[0807] A17, A18: See C. R. Davies, J. S. Davies, J. Chem. Soc. PerkinTrans 1, 1976, 2390-2394; K. Bevan, J. Chem. Soc. C, 1971, 514-522; K.Umezawa, K. Nakazawa, Y. Ikeda, H. Naganawa, S. Kondo, J. Org. Chem.1999, 64, 3034-3038 (R¹═R³═H); P. D. Williams, M. G. Bock, R. D. Tung,V. M. Garsky, D. S. Parlow, J. Med. Chem, 1992, 35, 3905-3918; K.Tamaki, K. Tanzawa, S. Kurihara, T. Oikawa, S. Monma, Chem. Pharm. Bull.1995, 43, 1883-1893 (R¹═R⁵═H; R³═COOBn); K. J. Hale, J. Cai V. Delisser,S. Manaviazar, S. A. Peak Tetrahedron 1996, 52, 1047 -1068; M. H. Chen,O. P. Goel, J.-W. Hyun, J. Magano, J. R. Rubin, Bioorg. Med. Chem. Lett.1999, 9, 1587-1592 (R¹═R⁵═H; R³═COOtBu); R. Baenteli, I. Brun, P. Hall,R. Metternich, Tetrahedron Lett. 1999, 40, 2109-2112 (R¹═R⁵═H; R³═COR);K. J. Hale, N. Jogiya, S. Manaviazar, Tetrahedron 1998, 39, 7163-7166(R¹═H; R³═COOBn; R⁵═OBn); T. Kamenecka, S. J. Danishewsky, Angew. Chem.Int. Ed. Engl. 1998, 37, 2995-2998(R¹═H; R³═COO(CH₂)₂SiMe₃;R⁵═OSiMe₂tBu.

[0808] A19: See Beilstein, Registry Number 648833 (R¹ ═R⁴═R⁸═H).Compounds of this type can be prepared according to Scheme 2.

[0809] A20: See D. Hagiwara, H. Miyake, N. Igari, M. Karino, Y. Maeda,J. Med. Chem. 1994, 37, 2090-2099 (R¹═H; R⁹═OH); Y. Arakawa, M. Yasuda,M. Ohnishi, S. Yoshifuji, Chem. Pharm. Bull. 1997, 45, 255-259 (R¹═H;R⁹═COOH); P. J. Murray, I. D. Starkey, Tetrahedron Lett. 1996, 37,1875-1878 (R¹═H; R⁹═(CH₂)₂NHCOCH₂Ph); K. Clinch, A. Vasella, R. Schauer,Tetrahedron Lett. 1987, 28, 6425-6428 (R¹═H; R⁹═NHAc).

[0810] A21: See A. Golubev, N. Sewald, K. Burger, Tetrahedron Lett.1995, 36, 2037-2040; F. Machetti, F. M. Cordero, F. DeSario, A. Guarna,A. Brandi, Tetrahedron Lett. 1996, 37, 4205-4208; P. L. Ornstein, D. D.Schoepp, M. B. Arnold, J. D. Leander, D. Lodge, J. Med. Chem. 1991, 34,90-97; R¹R⁶═H); P. D. Leeson, B. J. Williams, R Baker, T. Ludduwahetty,K. W. Moore, M. Rowley, J. Chem. Soc. Chem. Commun. 1990, 1578-1580; D.I. C. Scopes, N. F. Hayes, D. E. Bays, D. Belton, J. Brain, J. Med.Chem. 1992, 35, 490-501; H. Kessler, M. Kuehn, T. Löschner, Liebigs Ann.Chem. 1986, 1-20 (R¹═R⁶═H); C. Herdeis, W. Engel, Arch. Pharm. 1992, 7,419-424 (R¹═R⁶=Bn); C. Herdeis, W. Engel, Arch. Pharm. 1992, 411-418(R¹═COOMe; R⁶═H); C. Herdeis, W. Engel, Arch. Pharm. 1992, 419-424(R¹═COOMe; R⁶=Bn).

[0811] A22: See P. D. Leeson, B. J. Williams, R Baker, T. Ladduwahetty,K. W. Moore, M. Rowley, J. Chem. Soc. Chem. Comm. 1990, 1578-1580 (R¹═H;R¹⁰═NHOBn).

[0812] A23: See Beyerman, Boekee, Recl. Tray. Chim. Pays-Bas 1959, 78,648-653; D. R Adams, P. D. Bailey, I. D. Collier, J. D. Heffernan, S.Stokes J. Chem. Soc. Chem. Commun. 1996, 349-350; J. E. Baldwin, R. M.Adlington, C. Godfrey, D. W. Collins, J. G. Vaughan, J. Chem. Soc. Chem.Comm. 1993, 1434-1435 (R¹═R⁶═H); C. Herdeis, W. Engel, Arch. Pharm.1993, 297-302 (R¹═COOMe; R⁶═H).

[0813] A24: See Plieninger, Leonhäuser, Chem. Ber. 1959, 92, 1579-1584;D. W. Knight, N. Lewis, A. C. Share, D. Haigh, J. Chem. Soc. PerkinTrans.1 1998, 22, 3673-3684; J. Drummond, G. Johnson, D. G. Nickell, D.F. Ortwine, R. F. Bruns, B. Welbaum, J. Med. Chem. 1989, 32, 2116-2128;M. P. Moyer, P. L. Feldman, H. Rapoport, J. Org. Chem. 1985, 50,5223-5230 (R¹═R⁶═H); McElvain, Laughton, J. Am. Chem. Soc. 1951, 73,448-451 (R¹═H; R⁶—Ph); McElvain, Laughton, J. Am. Chem. Soc. 1951, 73,448-451 (R¹=Ph; R⁶═H);

[0814] A25: See L.-Y. Hu, T. R. Ryder, S. S. Nikam, E. Millerman, B. G.Szoke, M. F. Rafferty, Bioorg. Med. Chem. Lett. 1999, 9, 1121-1126; W.C. Lumma, R D. Hartman, W. S. Saari, E. L. Engelhardt, V. J. Lotti, C.A. Stone, J. Med. Chem. 1981, 24, 93-101; N. Hosten, M. J. O. Antenuis,Bull. Soc. Chim. Belg. 1988, 97, 48-50; C. F. Bigge, S. J. Hays, P. M.Novak, J. T. Drummond, G. Johnson, T. P. Bobovski, Tetrahedron Lett.1989, 30, 5193-5191; B. Aebischer, P. Frey, H.-P. Haerter, P. L.Herrling, W. Müller, Helv. Chim. Acta 1989, 72, 1043-1051; W. J.Hoeckstra, B. E. Maryanoff, B. P. Damiano, P. Andrade-Gordon, J. H.Cohen, M. J. Constanzo, B. J. Haertlein, L. R. Hecker, B. L. Hulshizer,J. A. Kaufnan, P. Keane, J. Med. Chem. 1999, 42, 5254-5265 (R¹═H;R¹¹═H); B. D. Dorsey, R. B. Levin, S. L. McDaniel, J. P. Vacca, J. P.Guare, J. Med. Chem. 1994, 37, 3443-3451; M. Cheng, B. De, S. Pikul, N.G. Almstaed, M. G. Natchus, M. V. Anastasio, S. J. McPhail, C. J.Snider, Y. O. Taiwo, L. Chen, C. M. Dunaway, J. Med. Chem. 2000, 43,369-380; R. Kuwano, Y. Ito, J. Org. Chem. 1999, 64, 1232-1237 (R¹═H;R¹¹═COOtBu); J. Kitchin, R. C. Bethell, N. Cammack, S. Dolan, D. N.Evans, J. Med. Chem. 1994, 37, 3707-3716 (R¹═H; R¹¹═COOPh); C. F. Bigge,S. J. Hays, P. M. Novak, J. T. Drummond, G. Johnson, T. P. Bobovski, J.Med. Chem. 1990, 33, 2916-2924 (R¹═H;R¹¹═COOtBu; —(CH₂)₃COOEt;—(CH₂)₃PO(Me)OH; —(CH₂PO(OH)₂; —(CH₂)₂PO(OEt)₂; —(CH₂)₂PO(OH)₂).

[0815] Compounds of type A25 can also be prepared according to Scheme 3:

[0816] A26: See Koegel, J. Biol. Chem. 1953, 201, 547 (R¹═R¹²═H).

[0817] A27: See G. Makara, G. R Marshall, Tetrahedron Lett. 1997, 38,5069-5072; R. N. Patel, A. Banedee, R L. Hanson, D. B. Brzozowski, L. W.Parker, L. J. Szarka, Tetrahedron: Asynmmetry 1999, 10, 31-36 (R¹═H;R¹³═OH, OtBu); J. E. Johanson, B. D. Cbristie, H. Rapoport, J. Org.Chem. 1981, 46, 4914-4920; N. Moss, J.-S. Duceppe, J.-M- Ferland, J.Gauthier, J. Med. Chem. 1996, 39, 2178-2187 (R¹═H; R¹³═CONHMe); G. M.Makara, G. R. Marshall, Tetrahedron Lett. 1997, 38, 5069-5072 (R¹═H;R¹³=SCH₂(4-MeO)C₆H₄).

[0818] A28: See A. Golubev, N. Sewald, K. Burger, Tetrahedron Lett.1995, 36, 2037-2040; P. L. Ornstein, D. D. Schoepp, M. B. Amold, 3. D.Leander, D. Lodge, J. Med. Chem. 1991, 34, 90-97 (R¹═R⁶═H); P. D.Leeson, B. J. Williams, R. Baker, T. Ladduwahetty, K. W. Moore, M.Rowley, J. Chem. Soc. Chem. Commun. 1990, 22, 1578-1580; C. Herdeis, W.Engel, Arch. Pharm. 1991, 324, 670 (R¹═H; R⁶=Me); C. Herdeis, W. Engel,Arch. Pharm. 1991, 324, 670 (R¹═COOMe; R⁶═H, Me).

[0819] A29: See Kawase, Masami, Chem. Pharm. Bull. 1997, 45, 1248-1253;I. G. C. Coutts, J. A. Hadfield, P. R Huddleston, J. Chem. Res.Miniprint, 1987, 9, 2472-2500; I. G. C. Coutts, J. A. Hadfield, P. R.Huddleston, J. Chem. Res. Miniprint, 1987, 9, 2472-2500; V. J. Hrubi, W.L. Cody, A. M. Castrucci M. E. Hadley, Collect. Czech. Chem. Commun.1988, 53, 2549-2573; R. T. Shwnan, R. B. Rothenberger, C. S. Campbell,G. F. Smith, D. S. Gifford-Moore, P. D. Gesellchen, J. Med. Chem. 1993,36, 314-319; M. Kawase, Y. Okada, H. Miyamae, Heterocycles, 1998, 48,285-294 (R¹═R⁸═H); Kawase, Masami, Chem. Pharm. Bull. 1997, 45,1248-1253 (R¹═H; R⁸=6,7-(MeO₂); D. F. Ortwine, T. C. Malone, C. F.Bigge, J. T. Drununond, C. Humblet, J. Med. Chem. 1992, 35, 1345-1370(R¹═H; R⁸=7-H₂PO(OEt)₂); E. J. Corey, D. Y. Gin, Tetrahedron Lett. 1996,37, 7163-7166 (R¹═CH₂SCOOtBu); P. Dostert, M. Varasi, A. DellaTorre, C.Monti, V. Rizzo, Eur. J. Med Chim. Ther. 1992, 27, 57-59 (R¹=Me;R⁸=6,7-(OH)₂); Z. Czamocki, D. Suh, D. B. McLean, P. G. Hultin,W. A.Szarek, Can. J. Chem. 1992, 70, 1555-1561; B. Schönenberger, A. Brossi,Helv. Chim. Acta 1986, 69, 1486-1497 (R¹=Me; R⁸=6-OH; 7-MeO); Hahn,Stiel, Chem. Ber. 1936, 69, 2627; M. Chbzanowska, B. Schönenberger, A.Brossi, J. L. Flippen-Anderson, Helv. Chim. Acta 1987, 70, 1721-1731; T.Hudlicky, J. Org. Chem. 1981, 46, 1738-1741 (R¹=Bn; R⁸=6,7-(OH)₂); A. I.Meyers, M. A. Gonzalez, V. Struzka, A. Akahane, J. Guiles, J. S. Warmus,Tetrahedron Lett. 1991, 32, 5501-5504 (R¹═CH₂(3,4-methylenedioxy)C₆H₃;R⁸=6,7-(OMe)₂).

[0820] A30 and A31 can be prepared according to Schemes 4 and 5.

[0821] A32 can be prepared according to P. W. Schiller, G. Weltrowska,T. M.-D. Nguyen, C. Lemieux, N. Nga, J. Med. Chem. 1991, 34, 3125-3132;V. S. Goodfellow, M. V. Marathe, K. G. Kuhlman, T. D. Fitzpatrick, D.Cuadrato, J. Med. Chem. 1996, 39, 1472-1484; G. Caliendo, F. Fiorino, P.Grieco, E. Perissutti, S. DeLuca, A. Guiliano, G. Santelli, D. Califano,B. Severino, V. Santagada, Farmacao, 1999, 54, 785-790; V. S.Goodfellow, M. V. Marathe, K G. Kuhlman, T. D. Fitzpatrick, D. Cuadro,J. Med. Chem. 1996, 39, 1472-1484 (R¹═R⁸═H); D. Tourwe, E. Mannekens, N.T. Trang, P. Verheyden, H. Jaspers, J. Med. Chem. 1998, 41, 5167-5176;A.-K. Szardenings, M. Gordeev, D. V. Patel, Tetrahedron Lett. 1996, 37,3635-3638; W. Wiczk, K. Stachowiak, P. Skurski, L. Lankiewicz, A.Michniewicz, A. Roy, J. Am. Chem. Soc. 1996, 118, 8300-8307; K.Verschuren, G. Toth, D. Tourwe, M. Lebl., G. van Binst, V. Hrubi,Synthesis 1992, 458-460 (R¹═H; R⁸═6-OH); P. L. Ornstein, M. B. Arnold,N. K. Augenstein, J. W. Paschal, J. Org. Chem. 1991, 56, 4388-4392(R¹═H; R⁸=6MeO); D. Ma, Z. Ma, A. P. Kozikowski, S. Pshenichlin, J. T.Wroblenski, Bioorg. Med. Lett. 1998, 8, 2447-2450 (R¹═H; R⁸=6-COOH); U.Schöllkopf, R. Hinrichs, R. Lonsky, Angew. Chem. 1987, 99, 137-138(R¹=Me; R⁸═H); B. O. Kammermeier, U. Lerch, C. Sommer, Synthesis 1992,1157-1160 (R¹═COOMe; R⁸═H); T. Gees, W. B. Schweizer, D. Seebach, Helv.Chim. Acta 1993, 76, 2640-2653 (R¹=Me; R⁸=6,7-(MeO₂).

[0822] A33: See Hinton, Mann, J. Chem. Soc. 1959, 599-608.

[0823] A34: See G. P. Zecchini, M. P. Paradisi, J. Heterocycl. Chem.1979, 16, 1589-1597; S. Cerrini, J. Chem. Soc. Perkin Trans.1, 1979,1013-1019; P. L. Ornstein, J. W. Paschal, P. D. Gesellchen, J. Org.Chem. 1990, 55, 738-741; G. M. Ksander, A. M. Yan, C. G. Diefenbacher,J. L. Stanton, J. Med. Chem. 1985, 28, 1606-1611; J. A. Robl, D. S.Karanewsky, M. M. Asaad, Tetrahedron Lett. 1995, 36, 1593-1596; S.Katayama, N. AC, R. Nagata, Tetrahedron: Asymmetry 1998, 9, 4295-4300(R¹═R⁸═H); K. Hino, Y. Nagai, H. Uno, Chem. Pharm. Bull. 1988, 36,2386-2400 (R¹=Me; R⁸═H).

[0824] A35: See Beilstein Registry Numbers: 530775, 883013 (R¹═R⁸═H).

[0825] A36: See R. W. Carling, P. D. Leeson, A. M. Moseley, R. Baker, A.C. Foster, J. Med. Chem. 1992, 35, 1942-1953; S. Kano, T. Ebata, S.Shibuya, J. Chem. Soc. Perkin Trans.1, 1980, 2105-2111 (R¹═R⁸═H); R. W.Carling, P. D. Leeson, A. M. Moseley, R. Baker, A. C. Foster, J. Med.Chem. 1992, 35, 1942-1953 (R¹═H; R⁸=5-Cl; 7-Cl).

[0826] A37: See Nagarajan, Indian J. Chem. 1973, 11, 112 (R¹═CH₂COOMe;R⁸═H).

[0827] A38: See R. Pauly, N. A. Sasaki, P. Potire, Tetrahedron Lett.1994, 35, 237-240; J. Podlech, D. Seebach, Liebigs Ann. Org. Bioorg.Chem. 1995, 7, 1217-1228; K. C. Nicolaou, G.-Q. Shi, K. Namoto, F.Bernal, J. Chem. Soc. Chem. Commun. 1998, 1757-1758 (R¹═H; R²═H).

[0828] A39: See Beilstein, Registry Number 782885.

[0829] A40; See F. P. J. C. Rutjes, N. M. Terhuis, H. Hiemstra, N. W.Speckamp, Tetrahedron 1993, 49, 8605-8628 (R¹═H; R³=Bn); compounds ofthis type can be prepared according to Scheme 6.

[0830] A41: Compounds of this type can be prepared according to Scheme7.

[0831] A42 to A46: Compounds of this type can be prepared according toScheme, 8 to 12. Key intermediate 34 and α-amino acid synthesisinvolving this building block include: R. M. Williams, M.-N. In,Tetrahedron Lett. 1988, 29, 6079-6082; R. M. Williams, M.-N. Im, J. Am.Chem. Soc.1991, 113, 9276-9286; J. F. Dellaria, B. D. Santarsiero,Tetrahedron Lett. 1988, 29, 6079-6082; J. F. Dellaria, B. D.Santarsiero, J. Org. Chem. 1989, 54, 3916-3926; J. E. Baldwin, V. Lee,C. J. Schofield, Synlett 1992, 249-251; J. E. Baldwin, V. Lee, C. J.Schofield, Heterocycles 1992, 34, 903-906.

[0832] A47: See P. BarTaclough, R. D. Farrant, D. Kettle, S. Smith, J.Chem. Res. Miniprint 1991, 11, 2876-2884 (R¹═R¹¹═H, Bn,—(CH₂)₂PO(OEt)₂).

[0833] A48: See A. Nouvet, M. Binard, F. Lamaty, J. Martinez, R. Lazaro,Tetrahedron 1999, 55, 4685-4698 (R¹═R¹²═H).

[0834] A49: See M. Y. Kolleganov, I. G. Kolleganova, M. D. Mitrofanova,L. I. Martynenko, P. P. Nazarov, V. I. Spitsyn, Bull. Acad. Sci. USSRDiv. Chem. Sci (Engl. Trans.) 1983, 32, 1293-1299; Izv. Akad. Nauk SSSRSer. Khim. 1983, 6, 1293-1299; V. P. Vasilev, T. D. Orlova, S. F.Ledenkov, J. Gen. Chem. USSR (Engl. Trans. 1989, 59, 1629-1634; Zh.Obshchi. Khim. 1989, 59, 1828-1833 (R¹═H; R¹²═CH(COOH)CH₂COOH).Compounds of type A49 can also be prepared according to Scheme 13.

[0835] A50 and A51: Compounds of these types can be prepared accordingto Schemes 14 and 15.

[0836] A53: See P. Barraclough, R. D. Fatrant, D. Kettle, S. Smith, J.Chem. Res. Miniprint 1991, 11, 2876-2884 (R¹═R¹¹═H; R¹═H; R¹¹=Bn,(CH₂)₃PO(OH)₂); —(CH₂)₃PO(Et)₂); J. I. Levin, J. F. DiJoseph, L. M.Killar, A. Sung, T. Walter, Bioorg. Med. Chem. Lett. 1998, 8, 2657-2662(R¹═H; R¹¹=4CF₃OC₆H₄CO).

[0837] A 52 and A54: Compounds of this type can be prepared according toSchemes 16 and 17.

[0838] A55 and A56: Compounds of this type can be prepared according toSchemes 18 and 19.

[0839] A57: Compounds of this type can be prepared according to Scheme20.

[0840] A58: See C.-H. Lee, H. Kohn, J. Org. Chem. 1990, 55, 6098-6104(R¹═R⁸═H).

[0841] A59: can be prepared according to Scheme 21.

[0842] A60: Compounds of this type can be prepared according to Scheme22.

[0843] A61: See D. R. Armour, K. M. Morriss, M. S. Congreve, A. B.Hawcock, Bioorg. Med. Chem. Lett. 1997, 7, 2037-2042 (R¹═R¹²═H).

[0844] A62: Compounds of this type can be prepared according to Scheme23.

[0845] A63: See S. E. Gibson, N. Guillo, R. J. Middleton, A. Thuiliez,M. J. Tozer, J. Chem. Soc. Perkin Trans.1, 1997, 4, 447-456; S. E.Gibson, N. Guillo, S. B. Kalindjan, M. J. Tozer, Bioorg. Med. Chem.Lett,. 1997, 7, 1289-1292 (R¹═H; R⁸═H); Beilstein Registry Number:459155 (R¹═H; R⁸=4,5-MeO₂).

[0846] A64: Compounds of this type can be prepared according to Scheme24.

[0847] A65 and A 67: Cotmpounds of these types can be prepared accordingto Schemes 25 and 26.

[0848] A66: See G. L. Grunewald, L. H. Dahanukar, J. Heterocycl. Chem.1994, 31, 1609-1618 (R¹═H; R⁸═H, 8-NO₂; C(1)=O).

[0849] A68: See Griesbeck, H. Mauder, I. Müller, Chem. Ber. 1992, 11,2467-2476; (R¹═R⁸═H; C(1)=O).

[0850] A69: R. Kreher, W. Gerhardt, Liebigs Ann. Chem. 1981, 240-247(R¹═R⁸═H).

[0851] As explained above, building blocks A70 belong to the class ofopen-chain α-substituted α-amino acids, A71 and A72 to the class of thethe corresponding β-amino acid analogues and A73-A104 to the class ofthe cyclic analogues of A70.

[0852] Building blocks of types A70 and A73-A104 have been synthesizedby several different general methods: by [2+2] cycloaddition of keteneswith imines (I. Ojima, H. J. C. Chen, X. Quin, Tetrahedron Lett. 1988,44, 5307-5318); by asymnmetric aldol reaction (Y. Ito, M. Sawamura, E.Shirakawa, K. Hayashikazi, T. Hayashi, Tetrahedron Lett. 1988, 29,235-238; by the oxazolidinone method (J. S. Amato, L. M. Weinstock, S.Karady, U.S. Pat. No. 4,508,921 A; M. Gander-Coquoz, D. Seebach, Helv.Chem. Acta 1988, 71, 224-236; A. K. Beck, D. Seebach, Chimia 1988, 42,142-144; D. Seebach, J. D. Aebi, M. Gander-Coquoz, R. Naef, Helv. Chim.Acta 1987, 70, 1194-1216; D. Seebach, A. Fadel, Helv. Chim. Acta 1995,68, 1243-1250; J. D. Aebi, D. Seebach, Helv. Chim. Acta 1985, 68,1507-1518; A. Fadel, J. Salaun, 8 Tetrahedron Lett. 1987, 28,2243-2246); by Schmidt—rearrangement of α,α-disubstituted α-ketoesters(G. I. Georg, X. Guan, J. Kant, Tetrahedron Lett. 1988, 29, 403-406);asymmetric synthesis via chiral Ni(II)-derived Schiff-bases (Y. N.Belokon, V. I. Baktmutov, N. I. Chemoglazova, K. A. Kochetov, S. V.Vitt, N. S. Garbalinskaya, V. M. Belikov, J. Chem. Soc Perkin Trans. 1,1988, 305-312; M. Kolb, J. Barth, Liebigs Ann. Chem. 1983, 1668-1688);by the bis-lactim ether synthesis (U. Schöllkopf, R. Hinrichs, R.Lonsky, Angew. Chem. 1987, 99, 137-138); by microbial resolution (K.Sakashita, I. Watanabe, JP 62/253397 A2) and by the hydantoin methodcombined with resolution of the racemic amino acids with chiralauxilliaries derived from L-phenylalanine amides (D. Obrecht, C.Spiegler, P. Schönholzer, K. Müller, H. Heimgartner, F. Stierli, Helv.Chim. Acta 1992, 75, 1666-1696; D. Obrecht, U. Bohdal, J. Daly, C.Lehmann, P. Schönholzer, K. Müller, Tetrahedron 1995, 51, 10883-10900;D. Obrecht, C. Lehmann, C. Ruffieux, P. Schönholzer, K. Mfiller, Helv.Chim. Acta 1995, 78, 1567-1587; D. Obrecht, U. Bohdal, C. Broger, D.Bur, C. Lehmann, R. Ruffieux, P. Schönholzer, C. Spiegler, Helv. Chim.Acta 1995, 78, 563-580; D. Obrecht, H. Karajiannis, C. Lehmann, P.Schönholzer, C. Spiegler, Helv. Chim. Acta 1995, 78, 703-714; D.Obrecht, M. Altorfer, C. Lehmann, P. Schönholzer, K. Müller, J. Org.Chem. 1996, 61, 4080-4086; D. Obrecht, C. Abrecht, M. Altorfer, U.Bohdal, A. Grieder, P. Pfyffer, K. Müller, Helv. Chim. Acta 1996, 79,1315-1337). The latter method has been especially useful in prepringboth enantiomers of building blocks of type A70 (see Scheme 27) andA73-A104 (see Scheme 28) in pure form.

[0853] The method depicted in Scheme 27 consists in treatment of theappropriate ketones 126 with KCN, (NH₄)₂CO₃ in a mixture ofethanol/water (E. Ware, J. Chem. Res. 1950, 46, 403; L. H. Goodson, I.L. Honigberg, J. J. Lehmann, W. H. Burton, J. Org. Chem. 1960, 25, 1920;S. N. Rastogi, J. S. Bindra, N. Anand, Ind. J. Chem. 1971, 1175) toyield the corresponding hydantoins 127, which were hydrolyzed withBa(OH) in water at 120-140° (R. Sarges, R. C. Schur, J. L. Belletire, M.J. Paterson, J. Med. Chem. 1988, 31, 230) to give 128 in high yields.Schotten-Baumrann acylation (Houben-Weyl, ‘Methoden der OrganischenChemie’, Volume XI/2, Stickstoff-Verbindungen II und III′, Georg TiemeVerlag, Stuttgart, pp 339) followed by cyclization withN,N′-dicyclohexyl carbodiimide gave azlactones 129 (D. Obrecht, U.Bohdal, C. Broger, D. Bur, C. Lehmann, R Ruffieux, P. Schönholzer, C.Spiegler, Helv. Chim. Acta 1995, 78, 563-580; D. Obrecht, C. Spiegler,P. Schönholzer, K. Müller, H. Heimgartner, F. Stierli, Helv. Chim. Acta1992, 75, 1666-1696). Alternatively, azlactones 129 could also beprepared starting from amino acids 130 and 131, Schotten-Baumanmacylation and cyclization with N,N′-dicyclohexyl carbodimide toazlactones 132 and 133 and alkylation to yield 129 (D. Obrecht, U.Bohdal, C. Broger, D. Bur, C. Lehmann, R. Ruffieux, P. Schönholzer, C.Spiegler, Helv. Chim. Acta 1995, 78, 563-580; D. Obrecht, C. Spiegler,P. Schönholzer, K. Müller, H. Heimgartner, F. Stierli, Helv. Chim. Acta1992, 75, 1666-1696)(see Scheme 1). Treatment of 129 withL-phenylalanine cyclohexylamide (D. Obrecht, U. Bohdal, C. Broger, D.Bur, C. Lehmann, R. Ruffieux, P. Schönholzer, C. Spiegler, Helv. Chim.Acta 1995, 78, 563-580) gave diastereomeric peptides 134 and 135, whichcould be conveniently separated by flash-chromatography orcrystallisation. Treatment of 134 and 135 with methanesulphonic acid inmethanol at 80° gave esters 136a and 136b which were converted into thecorresponding Fmoc-protected final building blocks 137a and 137b.

[0854] According to the general method described in Scheme 28 (D.Obrecht, U. Bohdal, C. Broger, D. Bur, C. Lehmann, R. Ruffieux, P.Schönholzer, C. Spiegler, Helv. Chim. Acta 1995, 78, 563-580; D.Obrecht, C. Spiegler, P. Schönholzer, K. Müller, H. Heimgartner, F.Stierli, Helv. Chim. Acta 1992, 75, 1666-1696) A73-A104 can be preparedstarting from the corresponding ketones 138, hydantoin formation (139)(E. Ware, J. Chem. Res. 1950, 46, 403; L. H. Goodson, I. L. Honigberg,J. J. Lehmann, W. H. Burton, J. Org. Chem. 1960, 25, 1920; S. N.Rastogi, J. S. Bindra, N. Anand, Ind. J. Chem. 1971, 1175; D. Obrecht,U. Bohdal, C. Broger, D. Bur, C. Lehmann, R. Ruffieux, P. Schönholzer,C. Spiegler, Helv. Chim. Acta 1995, 78, 563-580) and saponification(Ba(OH)₂) to yield the racemic amino acids 140, which uponSchotten-Baumann-acylation and cyclization withN,N′-dicyclohexylcarbodiimide gave azlactones 141. Reaction withL-phenylalanine cyclohexylamide (D. Obrecht, U. Bohdal, C. Broger, D.Bur, C. Lehmann, R. Ruffieux, P. Schönholzer, C. Spiegler, Helv. Chim.Acta 1995, 78, 563-580) gave the diastereomeric peptides 142 and 143,which were separated by flash-chromatography or crystallization.Treatment of 142 and 143 with methanesulphonic acid in methanol at 80°gave esters 144a and 144b which were converted into the correspondingsuitably protected aniino acid precursors 145a and 145b, ready forpeptide synthesis.

[0855] A71: Amino acid building blocks of this type (see formula 147)can be conveniently prepared from the corresponding disubstitutedsuccinates 146 by Curtius-rearrangement as shown in Scheme 29.

[0856] A71: See D. Seebach, S. Abele. T. Sifferlen, M. Haenggi, S.Gruner, P. Seiler, Helv. Chim. Acta 1998, 81, 2218-2243 (R¹⁸ and R¹⁹form: —(CH₂)₂—; —(CH₂)₃—; —(CH₂)₄—; —(CH₂)₅—; R²⁰═H); L. Ducrie, S.Reinelt P. Seiler, F. Diederich, D. R. Bolin, R. M. Campbell, G. L.Olson, Helv. Chim. Acta 1999, 82, 2432-2447; C. N. C. Drey, R. J. Ridge,J. Chem. Soc. Perkin Trans.1, 1981, 2468-2471; U. P. Dhokte, V. V. Khau,D. R. Hutchinson, M. J. Martinelli, Tetrahedron Lett. 1998, 39,8771-8774 (R¹⁸═R¹⁹=Me; R²⁰═H); D. L. Varie, D. k Hay, S. L. Andis, T. H.Corbett, Bioorg. Med. Chem. Lett. 1999, 9, 369-374 (R¹⁸═R¹⁹=Et); Testa,J. Org. Chem. 1959, 24, 1928 -1936 (R¹⁸=Et; R¹⁹=Ph); M. Haddad, C.Wakselman, J. Fluorine Chem. 1995, 73, 57-60 (R¹⁸=Me; R¹⁹═CF₃; R²⁰═H);T. Shono, K Tsubata, N. Okinaga, J. Org. Chem. 1984, 49, 1056-1059(R¹⁸═R¹⁹═R²⁰=Me); K. Ikeda, Y. Terao, M. Seldya, Chem. Pharm. Bull.1981, 29, 1747-1749 (R¹⁸ and R¹⁹ form: —(CH₂)_(s)—; R²⁰=Me).

[0857] Amino acid building blocks of type A72 can be convenientlyprepared by Arndt-Eistert C1-homologation of compounds of type A70according to Scheme 30.

[0858] A72: See Y. V. Zeifinan, J. Gen. Chem. USSR (Engl. Trans.) 1967,37, 2355-2363 (R¹⁸═R¹⁹═CF₃); W. R. Schoen, J. M. Pisano, K. Pendergast,M. J. Wyvratt, M. H. Fisher, J. Med. Chem. 1994, 37, 897-906; S.Thaisrivongs, D. T. Pals, D. W. DuCharme, S. Turner, G. L. DeGraaf, J.Med. Chem. 1991, 34, 655-642; T. K. Hansen, H. Thoegersen, B. S. Hansen,Bioorg. Med. Chem. Lett. 1997, 7, 2951-2954; R. J. DeVita, R. Bochis, A.J. Frontier, A. Kotliar, M. H. Fisher, J. Med. Chem. 1998, 41,1716-1728; D. Seebach, P. E. Ciceri, M. Overhand, B. Jaun, D. Rigo,Helv. Chim. Acta 1996, 79, 2043-2066; R. P. Nargund, K. H. Barakat, K.Cheng, W. Chan, B. R. Butler, A. A. Patchett, Bioorg. Med. Chem. Lett.1996, 6, 1265-1270 (R¹⁸═R¹⁹=Me); E. Altmann, K. Nebel, M. Mutter, Helv.Chimn. Acta 1991, 74, 800-806 (R¹⁸=Me; R¹⁹═COOMe).

[0859] A73: Compounds of this type can be prepared according to C.Mapelli, G. Tarocy, F. Schwitzer, C. H. Stammer, J. Org. Chem. 1989, 54,145-149 (R²¹=4-OHC₆H₄); F. Elrod, E. M. Holt, C. Mapelli, C. H. Stammer,J. Chem. Soc. Chem. Commun. 1988, 252-253 (R²¹═CH₂COOMe); R. E.Mitchell, M. C. Pirrung, G. M. McGeehan, Phytochemistry 1987, 26, 2695(R²¹═CH₂OH), J. Bland, A. Batolussi, C. H. Stammer, J. Org. Chem. 1988,53, 992-995 R²¹═CH₂NH₂). Additional derivatives of A73 have beendescribed by T. Wakamiya, Y. Oda, H. Fujita, T. Shiba, Tetrahedron Lett.1986, 27, 2143-2134; U. Schöllkopf, B. Hupfeld, R Gull, Angew. Chem.1986, 98, 755-756; J. E. Baldwin, R. M. Adlington, B. J. Rawlings,Tetrahedron Lett. 1985, 26, 481-484; D. Kalvin, K. Ramalinggar, R.Woodard, Synth. Comm. 1985, 15, 267-272 and L. M. Izquierdo, I. Arenal,M. Bemabe, E. Alvarez, Tetrahedron Lett. 1985, 41, 215-220.

[0860] A74: Compounds of this type can be prepared according to generalmethod described in Scheme 28 starting from the correspondingcyclobutanones.

[0861] A75 and A76: Compounds of this type can be prepared using thefollowing methods: P. Hughes, J. Clardy, J. Org. Chem. 1988, 53,4793-4796; E. A. Bell, M. Y. Qureshi, R. J. Pryce, D. H. Janzen, P.Letnke, J. Clardy, J. Am. Chem. Soc. 1980, 102, 1409; Y. Gaoni,Tetrahedron Lett. 1988, 29, 1591-1594; R. D. Allan, J. R. Haurahan, T.W. Hambley, G. A. R. Johnston, K. N. Mewett, A. D. Mitrovic, J. Med.Chem. 1990, 33, 2905-2915 (R²³═COOH); G. W. Fleet, J. A. Seijas, M.Vasquez Tato, Tetrahedron 1988, 44, 2077-2080 (R²³═CH₂OH).

[0862] A77: Compounds of this type can be prepared according to J. H.Burcihalter, G. Schmied, J. Pharm. Sci. 1966, 55, 443-445 (R²³=aryl).

[0863] A78: Compounds of this type can be prepared according to J. C.Watkins, P. Kroosgard-Larsen, T. Honor6, TIPS 1990, 11, 25-33; F.Trigalo, D. Brisson, R. Azeradc Tetrahedron Lett. 1988, 29, 6109(R²⁴═COOH).

[0864] A79: Compounds of this type can be prepared according to generalmethod described in Scheme 28 starting from the correspondingpyrrolidine-3-ones.

[0865] A80-A82: Compounds of this type can be prepared according to D.M. Walker, E. W. Logusch, Tetrahedron Lett. 1989, 30, 1181-1184; Y.Morimoto, K. Achiwa, Chem. Pharm. Bull. 1989, 35, 3845-3849; J.Yoshimura, S. Kondo, M. Thara, H. Hashimoto, Carbohydrate Res. 1982, 99,129-142.

[0866] A83: Compounds of this type can be prepared according to generalmethod described in Scheme 28 starting from the correspondingpyrazoline4-ones.

[0867] A84: Compounds of this type can be prepared according to R. M.Pinder, B. H. Butcher, D. H. Buxton, D. J. Howells, J. Med. Chem. 1971,14, 892-893; D. Obrecht, U. Bohdal, C. Broger, D. Bur, C. Lehmann, R.Ruffieux, P. Schönholzer, C. Spiegler, Helv. Chim. Acta 1995, 78,563-580.

[0868] A85: Compounds of this type can be prepared according to generalmethod described in Scheme 28 starting from the correspondingindane-1,3diones.

[0869] A86: Compounds of this type can be prepared according to generalmethod described in Scheme 28 starting from the correspondingindane-2-ones.

[0870] A87: Compounds of this type and analogues thereof can be preparedaccording to C. Cativiela, M. D. Diaz de Villegas, A. Avenoza, J. M.Peregrina, Tetrahedron 1993, 47, 10987-10996; C. Cativiela, P. Lopez, J.A. Mayoral, Tetrahedron Assymmetry 1990, 1, 379; C. Cativiela, 1. A.Mayoral, A. Avenoza, M. Gonzalez, M. A. Rey, Synthesis 1990, 1114.

[0871] A87 and A88: Compounds of this type can be prepared according toL. Munday, J. Chem. Soc. 1961, 4372; J. Ansell, D. Morgan, H. C. Price,Tetrahedron Lett. 1978, 47, 4615-4616.

[0872] A89: Compounds of this type can be prepared according to generalmethod described in Scheme 28 stating from the correspondingpiperidine-3-ones.

[0873] A90: Compounds of this type can be prepared according to generalmethod described in Scheme 28 starting from the correspondingtetahydrothiapyran-3-ones.

[0874] A91: Compounds of this type can be prepared according to generalmethod described in Scheme 28 starting from the correspondingtetrahydropyran-3-ones.

[0875] A92: Compounds of this type can be prepared according to generalmethod described in Scheme 28 starting from the correspondingpiperidine-2,5-diones.

[0876] A93: Compounds of this type can be prepared according to generalmethod described in Scheme 28 starting from the correspondingcyclohexanones.

[0877] A94: Compounds of this type can be prepared according to J. Org.Chem. 1990, 55, 4208.

[0878] A95: Compounds of this type can be prepared according to N.J.Lewis, R. L. Inloes, J. Hes, R. H. Matthews, G. Milo, J. Med. Chem.1978, 21, 1070-1073.

[0879] A96: Compounds of this type can be prepared according to generalmethod described in Scheme 28 starting from the correspondingtetrahydropyrann4-ones.

[0880] A97: Compounds of this type can be prepared according to generalmethod described in Scheme 28 starting from the correspondingpiperidine-2,4diones.

[0881] A98: Compounds of this type can be prepared according to generalmethod described in Scheme 28 starting from the corresponding1-tetralones (D. Obrecht, C. Spiegler, P. Schönholzer, K. Müller, H.Heimgartner, F. Stierli, Helv. Chim. Acta 1992, 75, 1666-1696).

[0882] A99: Compounds of this type can be prepared according to generalmethod described in Scheme 28 starting from the correspondingtetraline-1,4-dione mono-diethylacetals.

[0883] A100: Compounds of this type can be prepared according to generalmethod described in Scheme 28 starting from the correspondingtetrahydroquinolin-4-ones.

[0884] A101: Compounds of this type can be prepared according to generalmethod described in Scheme 28 starting from the correspondingtetrahydroquinoline-2,4-diones.

[0885] A102: Compounds of this type can be prepared according to K.Ishizumi, N. Ohashi, N. Tanno, J. Org. Chem. 1987, 52, 4477-4485; D.Obrecht, U. Bohdal, C. Broger, D. Bur, C. Lehmann, R. Ruffieux, P.SchönholzeT, C. Spiegler, Helv. Chim. Acta 1995, 78, 563-580; D.Obrecht, C. Spiegler, P. Schönholzer, K. Müller, H. Heimgartner, F.Stierli, Helv. Chim. Acta 1992, 75, 1666-1696; D. R. Haines, R. W.Fuller, S. Ahmad, D. T. Vistica, V. E. Marquez, J. Med. Chem. 1987, 30,542-547; T. Decks, P. A. Crooks, R. D. Waigh, J. Pharm. Sci 1984, 73,457-460; I. A. Blair, L. N. Mander, Austr. J. Chem. 1979, 32, 1055-1065.

[0886] Overviews dealing with building blocks of types (b)-(p) are: S.Hanessian, G. McNaughton-Smith, H.-G. Lombart, W. D. Lubell, Tetrahedron1997, 38, 12789-12854; D. Obrecht, M. Altorfer, J. A. Robinson, “NovelPeptide Mimetic Building Blocks and Strategies for Efficient LeadFinding”, Adv. Med. Chem. 1999, Vol.4, 1-68

[0887] Templates of type (b1) can be prepared according to Schemes 31and 32.

[0888] i: Treatment of 150 with a dehydrating reagent such asthionylchloride in methanol at an elevated temperature, conveniently atreflux.

[0889] ii: Introduction of Boc, e.g. using di-tert.butyl dicarbonate andtriethylamine in a suitable solvent such as dichloromethane; any othersuitable N-protecting group (not shown in Reaction Scheme 31) can beintroduced in an analogous manner.

[0890] iii: Reaction of formed product with phthalimide, diethyldiazodicarboxylate and triphenylphoshine under standard Mitsunobuconditions (Mitsunobu, O.; Wada, M.; Sano, T. J. J. Am. Chem. Soc. 1972,94, 672) to conveniently yield 151.

[0891] iv: Treatment of 151 with trifluoracetic acid in dichloromethane.

[0892] v: 152 is coupled under standard peptide coupling conditions withCbz-Asp(tBu)OH in DMF with reagents such as HBTU and1-hydroxybenztriazole (HOBt) with a base such as diisopropylethylamineto yield 153.

[0893] vi: Removal of the Cbz-group, conveniently by hydrogenation usingH₂ and a catalyst such as Palladium on charcoal, in solvents such asethanol, DMP and ethyl acetate.

[0894] vii: The phthalimide group is cleaved off from the resultingproduct, conveniently by treatment with hydrazine in a suitable solventsuch as ethanol at an elevated temperature, suitably at about 80° C. andcleavage of the formed product with trifluoracetic acid in CH₂Cl₂.

[0895] viii: The formed amino acid is conveniently protected withreagents such as 9-fluorenylmethoxcarbonyl chloride or9-fluorenylmethoxcarbonyl succininide using a base such as sodiumcarbonate or triethylamine in a suitable solvent or mixture of solventssuch as dioxane and water, or dichloromethane to yield 154 as describedby Bisang, C.; Weber, C.; Robinson, J. A. Helv. Chim. Acta 1996, 79,1825-1942.

[0896] i: Treatment of 150 with a dehydrating reagent such as thionylchloride in a suitable solvent such as methanol at an elevatedtemperature, conveniently at reflux.

[0897] ii: The resulting amino acid ester is N-protected under standardconditions for introducing the Cbz-group, e.g. using benzyloxycarbonylchloride and triethylamine in a suitable solvent such asdichloromethane.

[0898] iii: The Cbz-protected amino acid methyl ester is treated withtrimethylsilylchloride and a base such as triethylamine in a solventsuch as tetrahydrofuran, cooled, conveniently to about −78° C., followedby reaction with a strong base such as lithium diisopropylamide orlithium hexamethyldisilylazide and tert.-butyl bromoacetate yielding 155as a mixture of diastereomers as described by Bisang, C.; Jiang, L.;Freund, E.; Emery, F.; Bauch, C.; Matile, H,; Pluschke, G.; Robinson, J.A. J. Am. Chem. Soc. 1998, 120, 7439-7449; Emery, F.; Bisang, C.; Favre,M.; Jiang, L.; Robinson, J. A. J. Chem. Soc. Chem. Commun. 1996,2155-2156.

[0899] iv: Reaction of 155 with phthalimide, diethyl diazodicarboxylateand triphenylphosphine under standard Mitsunobu conditions (Mitsunobu,O.; Wada, M.; Sano, T. J. J. Am. Chem. Soc. 1972, 94, 672).

[0900] v: The resulting product is hydrogenated using H₂ and a suitablecatalyst such as palladium on charcoal in a solvent such as ethylacetate, DMF or ethanol; subsequently separation of diastereomers takesplace and yields 156.

[0901] vi: 156 is coupled with Fmoc-Asp(allyl)OH under standard peptidecoupling conditions using reagents such as HATU, HOAt and a base such asdiisopropylethylamine in a suitable solvent such as DMF.

[0902] vii: Cyclization, conveniently with DBU in DMF to yield 157.

[0903] viii: The phthalimide group is cleaved off from resultingproduct, conveniently by hydrazinolysis, e.g. treatment withmethylhydrazine in a suitable solvent such as DMF.

[0904] ix: The formed product is conveniently protected with reagentssuch as 9-fluorenylmethoxcarbonyl chloride or 9-fluorenylmethoxcarbanylsuccinimide using a base such as sodium carbonate or triethylamine in asuitable solvent or mixture of solvents such as dioxane and water, ordichloromethane to yield 158.

[0905] x: Standard removal of an allyl ester group using e.g.palladium(0) as catalyst gives 159.

[0906] Templates of type (b2) can be prepared according to Scheme 33.

[0907] i: 160 (obtainable from Vitamin C as described by Hubschwerlen,C. (Synthesis 1986, 962) is treated with phthalimide, diethyldiazodicarboxylate and triphenylphoshine under standard Mitsunobuconditions (Mitsunobu, O.; Wada, M.; Sano, T. J. J. Am. Chem. Soc. 1972,94, 672).

[0908] ii: The phthalimide group is cleaved off from the product,conveniently by hydrazinolysis, e.g. by treatment with methylhydrazinein a suitable solvent such as DMF.

[0909] iii: The amino group is protected by treatment with abenzoylating reagent such as benzoic acid anhydride or benzoylchlorideand a base such as triethylamine or 4-dimethylaminopyridine in asuitable solvent such as dichloromethane or DMP.

[0910] iv: Removal of the 2,4-dimethoxybenzyl group, e.g. with K₂S₂O₈and Na₂HPO₄ in aqueous acetonitrile at an elevated temperature, e.g. atabout 80° C.

[0911] v: Introduction of a tert-butoxycarbonyl group using e.g.di-tert.-butyloxycarbonyl dicarbonate, triethylamine and a catalyticamount of 4-dimethylaminopyridine in a suitable solvent such asdichloromethane.

[0912] vi: Reaction with aqueous sodium carbonate in tetrahydrofuranfollowed by acidification.

[0913] vii: Esterification of the carboxylic acid group, convenientlywith diazomethane in a suitable solvent such as diethylether yielding161.

[0914] viii Removal of the Cbz-group, conveniently by hydrogenation withH₂ in the presence of a catalyst such as palladium on charcoal in asolvent such as DMF to yield 161 as described by Pfeifer, M.; Robinson,J. A. J. Chem. Soc. Chem. Commun. 1998, 1977.

[0915] ix: 161 is coupled under standard peptide coupling conditionswith Cbz-Asp(tBu)OH in DMF with reagents such as HBTU and1-hydroxybenztriazole with a base such as diisopropylethylamine to yield162 as described by Pfeifer, M.; Robinson, J. A. J. Chem. Soc. Chem.Commun. 1998, 1977.

[0916] x: Removal of the Cbz-group, e.g. by hydrogenation using H₂ and acatalyst such as palladium on charcoal under standard conditions, yields163 as described by Pfeifer, M.; Robinson, J. A, J. Chem. Soc. Chem.Commun. 1998, 1977.

[0917] xi: Cleavage of the tert.-butyl ester and tert.-butyloxycarbonylgroups, conveniently using trifluoracetic acid in dichloromethane or 4Nhydrochloric acid in dioxane.

[0918] xii: The intermediate free amino acid formed is convenientlyprotected with reagents such as 9-fluorenylmethoxcarbonyl chloride or9-fluorenylmethoxcarbonyl succinimide using a base such as sodiumcarbonate or triethylamine in a suitable solvent or mixture of solventssuch as dioxane and water, or dichloromethane to yield 164 as describedby Pfeifer, M.; Robinson, J. A. J. Chem. Soc. Chem. Commun. 1998, 1977.

[0919] Templates of type (c1) can be prepared according to Schemes 34 to37.

[0920] i: 166 can be synthesized from 165 according to P. Waldmeier,“Solid-supported synthesis of highly substituted xanthene-derivedtemplates for the synthesis of β-turn stabilized cyclic peptidelibraries”, PhD-thesis, University of Zurich, 1996. For cleaving thephthalimide group 166 is conveniently submitted to hydrazinolysis, e.g.by treatment with hydrazine hydrate in a suitable solvent such asethanol at an elevated temperature, e.g. at about 80° C.

[0921] ii: The intermediate aminonitrile is saponified, convenientlyunder basic conditions, e.g. with aqueous sodium hydroxide in a suitablesolvent such as ethanol at an elevated temperature, conveniently underreflux, to yield 167.

[0922] iii: The intermediate free amino acid formed is convenientlyprotected with reagents such as 9-fluorenylmethoxcarbonyl chloride or9-fluorenylmethoxcarbonyl succinimide using a base such as sodiumcarbonate or triethylamine in a suitable solvent or mixture of solventssuch as dioxane and water, or dichloromethane to yield 168 as describedby P. Waldmeier, “Solid-supported synthesis of highly substitutedxanthene-derived templates for the synthesis of β-turn stabilized cyclicpeptide libraries”, PhD-thesis, University of Zurich, 1996.

[0923] iv: Regioselective bromination of 167 is performed preferablywith bromine in acetic acid and dichloromethane. In a similar fashionR³⁷═NO₂ can be introduced by treatment with HNO₃ in acetic acid andR³⁷═CH₂—NPht by treatment with hydroxymethyl phthalimide in H₂SO₄.

[0924] v: The amino group is conveniently Cbz-protected with reagentssuch as benzyloxycarbonyl chloride or succinimide in a suitable solventsuch as dioxane in presence of a base such as aqueous sodium hydroxide.

[0925] vi: The carboxylic acid group is esterified, preferably with DBUand methyl iodide in DMF to yield 169.

[0926] vii: Introduction of lower alkyl, substituted lower alkyl andaryl substituents (R³⁷), conveniently by palladium(0)-catalyzedStille-(Stille, J. K. Angew. Chem. 1986, 68, 504) and Suzuki-couplings(Oh-e, T.; Mijaura, N.; Suzuki, A. J. Org. Chem. 1993, 58, 2201). Anyother functionalization known for aryl bromides can be employed forintroduction of substituents R³⁷.

[0927] viii: Removal of the Cbz-group, e.g. by hydrogenation using H²and a catalyst such as palladium on charcoal in a suitable solvent suchas ethanol, DMF and ethyl acetate.

[0928] ix: Hydrolysis of the ester group, conveniently under acidicconditions, e.g. with 25% aqueous hydrochloric acid in a suitablesolvent such as dioxane at an elevated temperature, preferably at about100° C.

[0929] x: The intermediate free amino acid formed is convenientlyprotected with reagents such as 9-fluorenylmethoxcarbonyl chloride or9-fluorenylmethoxcarbonyl succinimide using a base such as sodiumcarbonate or triethylamine in a suitable solvent or mixture of solventssuch as dioxane and water, or dichloromethane to yield 170.

[0930] i: Double ortho-bromination of 171 is performed preferably withexcess bromine in acetic acid and dichloromethane. In a similar fashionR³⁷═R³⁸═NO₂ can be introduced by treatment with HNO₃ in acetic acid andR³⁷═R³⁸═CH₂—NPht by treatment with hydroxymethyl phthalimide in H₂SO₄.

[0931] ii: The amino group is protected, conveniently Cbz-protected,with reagents such as benzyloxycarbonyl chloride or succinimide in asuitable solvent such as dioxane in the presence of a base such asaqueous sodium hydroxide.

[0932] iii: The carboxylic acid group is esterified, preferably with DBUand methyl iodide in DMF to yield 172.

[0933] iv: Introduction of lower alkyl, substituted lower allyl and arylsubstituents (R³⁷═R³⁸), e.g. by palladium(0)-catalyzed Stille-(Stifle,J. K. Angew. Chem. 1986, 68, 504) and Suzuki-couplings (Oh-e, T.;Mijaura, N.; Suzuki, A. J. Org. Chem. 1993, 58, 2201).

[0934] Any other functionalization known for aryl brormides can beemployed for introduction of substituents R³⁷ and R³⁸.

[0935] v: Removal of the Cbz-group of 173, e.g. by hydrogenation usingH₂ and a catalyst such as palladium on charcoal in a suitable solventsuch as ethanol, DMF or ethyl acetate.

[0936] vi: Hydrolysis of the ester group, conveniently under acidicconditions, e.g. with 25% aqueous hydrochloric acid in a suitablesolvent such as dioxane at an elevated temperature, conveniently atabout 100° C.

[0937] vii: The intermediate free amino acid formed is convenientlyprotected with reagents such as 9-fluorenylmethoxcarbonyl chloride or9-fluorenylmethoxcarbonyl succinimide using a base such as sodiumcarbonate or triethylamine in a suitable solvent or mixture of solventssuch as dioxane and water, or dichloromethane to yield 174.

[0938] i: Cleavage of the methoxy groups of 166, preferably by treatmentwith an excess of boron tribromide in a suitable solvent such asdichloromethane.

[0939] ii: Hydrolysis of the cyano group under acidic conditions,preferably with 25% aqueous hydrochloric acid in a suitable solvent suchas dioxane at an elevated temperature, conveniently at about 100° C.

[0940] iii: The resulting acid is treated with a dehydrating agent suchas thionyl chloride in a suitable solvent such as dioxane to yield 175.

[0941] iv: Treatment of 175 with an appropriate triflating reagent,preferably trifluoromethanesulfonic acid anhydride in the presence of abase such as 2,6-di-tert.-butyl-pyridine in a suitable solvent such asdichloromethane.

[0942] v: Heating of the intermediate, conveniently in a suitablesolvent such as methanol.

[0943] vi: Introduction of lower alkyl or aryl-lower alkyl (R³⁵) byalkylation to yield 177. Any other functionalization known for phenolgroups can be employed for introduction of substituents R³⁵.

[0944] vii: Introduction of lower alkyl or aryl (R³⁶), conveniently bypalladium(0)-catalyzed Suzuki-coupling (Ohe, T.; Mijaura, N.; Suzuki, A.J. Org. Chem. 1993, 58, 2201) to yield 178. Any other functionalizationknown for aryl bromides can be employed for introduction of substituentsR³⁶.

[0945] viii: Hydrolysis of the ester group under acidic conditions,conveniently with 25% aqueous hydrochloric acid in a suitable solventsuch as dioxane at an elevated temperature, e.g. at about 100° C.

[0946] ix: Cleavage of the phthalimido group, conveniently byhydrazinolysis, e.g. with hydrazine hydrate in a suitable solvent suchas ethanol.

[0947] x: The intermediate free amino acid formed is convenientlyprotected with reagents such as 9-fluorenylmethoxcarbonyl chloride or9-fluorenylmethoxcarbonyl succinimide using a base such as sodiumcarbonate or triethylamine in a suitable solvent or mixture of solventssuch as dioxane and water, or dichloromethane to yield 179.

[0948] i: Bromination of 175 using reagents such as bromine in a mixtureof acetic acid and dichloromethane at temperatures ranging from about 0°C. to about room temperature.

[0949] ii: Benzoylation of the hydroxy group using an appropriateacylating agent such as benzoyl chloride or benzoic acid anhydride, abase such as pyridine or triethylamine and a suitable solvent such asdichloromethane to yield 180.

[0950] iii: 180 is treated with methanol and a catalytic amount of anacidic catalyst such as camphor sulfonic acid under heating.

[0951] iv: Introduction of lower alkyl or aryl-lower alkyl (R³⁵) byalkylation using a base such as sodium hydride or potassiumtert.-butoxide in a solvent such as tetrahydrofuran, dimethoxyethane orDMF gives 181.

[0952] v: Lower alkyl, substituted lower alkyl and aryl substituents(R³⁸) are introduced, e.g. by palladium(0)-catalyzed Stille-(Stille, J.K. Angew. Chem. 1986, 68, 504) and Suzuki-couplings (Oh-e, T.; Mijaura,N.; Suzuki, A. J. Org. Chem. 1993, 58, 2201). Any otherfunctionalization known for aryl bromides can be employed forintroduction of substituents R³⁸.

[0953] vi: For cleaving the benzyloxy group the intermediate isconveniently heated with sodium cyanide adsorbed on aluminum oxide andmethanol.

[0954] vii: Treatment with an appropriate triflating reagent, preferablytrifluoromethanesulfonic acid anhydride, in the presence of a base suchas 2,6di-tert-butyl-pyridine in a suitable solvent such asdichloromethane.

[0955] viii: Introduction of lower alkyl and aryl substituents (R³⁶),e.g. by palladium(0)-catalyzed Stille-(Stille, J. K. Angew. Chem. 1986,68, 504) and Suzuki-couplings (Oh-e, T.; Mijaura, N.; Suzuki, A. J. Org.Chem. 1993, 58, 2201) yields 182. Any other functionalization known foraryl bromides can be employed for introduction of substituents R³⁶.

[0956] ix: Bromination under standard conditions such as using brominein acetic acid and dichloromethane at temperatures ranging from about 0°C. to about room temperature.

[0957] x: Lower alkyl, substituted lower alkyl and aryl substituents(R³⁷) are introduced, e.g. by palladium(0)-catalyzed Stille-(Stille, J.K. Angew. Chem. 1986, 68, 504) and Suzuki-couplings (Oh-e, T.; Mijaura,N.; Suzuki, A. J. Org. Chem. 1993, 58, 2201) to yield 184. Any otherfunctionalization known for aryl bromides can be employed forintroduction of substituents R³⁷.

[0958] xi: The ester group is hydrolyzed under acidic conditions,conveniently with 25% aqueous hydrochloric acid in a suitable solventsuch as dioxane at an elevated temperature, e.g. at about 100° C.

[0959] xii: The phthalimido group is cleaved, e.g. by hydrazinolysis,conveniently with hydrazine hydrate in a suitable solvent such asethanol.

[0960] xiii: The intermediate free amino acid formed is convenientlyprotected with reagents such as 9-fluorenylmethoxcarbonyl chloride or9-fluorenylmethoxcarbonyl succinimide using a base such as sodiumcarbonate or triethylamine in a suitable solvent or mixture of solventssuch as dioxane and water, or dichloromethane to yield 185.

[0961] Templates of type (c2) can be prepared as shown in Schemes 38 and39.

[0962] i: 3,7-Dimethoxyphenothiazine 186 is prepared and converted into187 according to Müller, K.; Obrecht, D.; Knierzinger, A.; Spiegler, C.;Bannwarth, W.; Trzeciak, A.; Englert, G.; Labhardt, A.; Schönholzer, P.Perspectives in Medicinal Chemistry, Editor Testa, B.; Kyburz, E.;Fubrer, W.; Giger, R., Weinheimn, New York, Basel, Cambridge: VerlagHelvetica Chimica Acta, 1993, 513-531; Bannwarth, W.; Gerber, F.;Grieder, A.; Knierzinger, A; Müller, K.; Obrecht. D.; Trzeciak, A. Can.Pat. Appl. CA2101599 (131 pages). The benzyl group is cleaved off from187 conveniently by hydrogenation, e.g. with H₂ and a catalyst such aspalladium on charcoal in a suitable solvent such as ethanol, DMF orethyl acetate.

[0963] ii: Introduction of lower alkyl (R⁴³) by alkylation using anappropriate alkylating agent (R⁴³—X′; X′═OTf, Br, I) and strong basessuch as sodium amide in liquid ammonia or sodium hydride intetrahydrofuran, dioxan or DMF in the presence of a phase transfercatalyst such as TDA-I. In a similar manner substituted lower alkyl(R⁴³) can be introduced; thus, for example R⁴³═CH₂COOR⁵⁵ andCH₂CH₂COOR⁵⁵ can be introduced by treatment with the appropriate 2-haloacetic and, respectively, 3-halo propionic acid derivatives. Any otherfunctionalization known for diarylamines can be employed forintroduction of substituents R⁴³.

[0964] iii: Cleavage of the methoxy groups of 188, conveniently bytreatment with an excess of boron tribromide in a suitable solvent suchas dichloromethane at temperatures ranging from about −20° C. to aboutroom temperature.

[0965] iv: For the introduction of lower alkyl, substituted lower allylor aryl-lower alkyl substituents (R³⁹ and R⁴⁰) the intermediatebis-phenol derivative is conveniently reacted with a reagent of theformula R³⁹— and R⁴⁰—X′ (X′═OTf, Br, I) in the presence of strong basessuch as sodium hydride in tetrahydrofuran, dioxan or DMF in the presenceof a phase transfer catalyst such as TDA-I. Any other functionalizationknown for phenol groups can be employed for introduction of substituentsR³⁹ and R⁴⁰.

[0966] v: The cyano group of 188 and, respectively, 189 is hydrolyzed,conveniently under acidic conditions, e.g. with 25% aqueous hydrochloricacid in a suitable solvent such as dioxane at an elevated temperature,e.g. at about 100° C.

[0967] vi: The phthalimide group of the intermediate is cleaved,conveniently by hydrazinolysis, e.g. with hydrazine hydrate in asuitable solvent such as ethanol.

[0968] vii: The free amino group is conveniently protected with reagentssuch as 9-fluorenylmethoxcarbonyl chloride or 9-fluorenylmethoxcarbonylsuccinimide using a base such as sodium carbonate or triethylamine in asuitable solvent or mixture of solvents such as dioxane and water, ordichloromethane to yield 190 and, respectively, 191.

[0969] i: The cyano group of 188 is hydrolyzed, conveniently underacidic conditions, e.g. with 25% aqueous hydrochloric acid in a suitablesolvent such as dioxane at an elevated temperature, e.g. at about 100°C.

[0970] ii: The phthalimide group of the intermediate is cleaved,conveniently by hydrazinolysis, e.g. with hydrazine hydrate in asuitable solvent such as ethanol to yield 192.

[0971] iii: Double ortho-bromination of 192 is performed preferably withexcess bromine in acetic acid and dichloromethane. In a similar fashionR⁴¹═R⁴²═NO₂ can be introduced by treatment with HNO₃ in acetic acid andR⁴¹═R⁴²═CH₂—NPht by treatment with hydroxymethyl phthalimide in H₂SO₄.Any other functionalization by electrophilic aromatic substitution knowncan be employed for introduction of substituents R⁴¹ and R⁴².

[0972] iv: The amino group is protected, conveniently Cbz-protected,with reagents such as benzyloxycarbonyl chloride or succinimide in asuitable solvent such as dioxane in the presence of a base such asaqueous sodium hydroxide.

[0973] v: The carboxylic acid group is esterified, preferably with DBUand methyl iodide in DMF to yield 193.

[0974] vi: Regioselective bromination of 192 is performed preferablywith bromine in acetic acid and dichloromethane. In a similar fashionR⁴¹═NO₂ can be introduced by treatment with HNO₃ in acetic acid andR⁴¹═CH₂—NPt by treatment with hydroxymethyl phthalimide in H₂SO₄. Anyother functionalization by electrophilic aromatic substitution known canbe employed for introduction of substituents R⁴¹.

[0975] vii: The amino group is conveniently Cbz-protected with reagentssuch as benzyloxycarbonyl chloride or succinimide in a suitable solventsuch as dioxane in presence of a base such as aqueous sodium hydroxide.

[0976] viii: The carboxylic acid group is esterified, preferably withDBU and methyl iodide in DMF to yield 194.

[0977] ix: Introduction of lower alkyl, substituted lower alkyl and arylsubstituents (R⁴¹) for 194 and (R⁴¹ and R⁴²) for 193, conveniently bypalladium(0)-catalyzed Stille-(Stille, J. K. Angew. Chem. 1986, 68, 504)and Suzuki-couplings (Oh-e, T.; Mijaura, N.; Suzuki, A. J. Org. Chem.1993, 58, 2201). Any other functionalization known for aryl bromides canbe employed for introduction of substituents R⁴¹ and R⁴².

[0978] x: Removal of the Cbz-group, e.g. by hydrogenation using H₂ and acatalyst such as palladium on charcoal in a suitable solvent such asethanol, DMF and ethyl acetate.

[0979] xi: Hydrolysis of the ester group, conveniently under acidicconditions, e.g. with 25% aqueous hydrochloric acid in a suitablesolvent such as dioxane at an elevated temperature, preferably at about100° C.

[0980] xii: The intermediate free amino acid formed is convenientlyprotected with reagents such as 9-fluorenylmethoxcarbonyl chloride or9-fluorenylmethoxcarbonyl succinimide using a base such as sodiumcarbonate or triethylamine in a suitable solvent or mixture of solventssuch as dioxane and water, or dichloromethane to yield 195 and 196.

[0981] Templates of type (c3) can be prepared as shown in Schemes 40 and41.

[0982] i: 197 can be prepared from commercial resorufin and covertedinto 198 according to Müller, K.; Obrecht, D.; Knierzinger, A.;Spiegler, C.; Bannwarth, W.; Trzeciak, A.; Englert, G.; Labhardt, A.;Schönholzer, P. Perspectives in Medicinal Chemistry, Editor Testa, B.;Kyburz, E.; Fubrer, W.; Giger, R., Weinheim, New York, Basel, Cambridge:Verlag Helvetica Chimica Acta, 1993, 513-531; Bannwarth, W.; Gerber, F.;Grieder, A.; Knierzinger, A.; Müller, K.; Obrecht. D.; Trzeciak, A. Can.Pat. Appl. CA2101599 (131 pages). For splitting off the benzyl group 198is conveniently hydrogenated e.g. with H₂ and a catalyst such aspalladium on charcoal in a suitable solvent such as ethanol, DMF orethyl acetate.

[0983] ii: Introduction of lower alkyl (R⁴³) by alkylation with R⁴³—X′(X′═OTf, Br, I) using strong bases such as sodium amide in liquidammonia or sodium hydride in tetrahydrofuran, dioxan or DMF in thepresence of a phase transfer catalyst such as TDA-I to yield 199. In asimilar manner substituted lower alkyl (R⁴³) can be introduced; thus,for example, R⁴³═CH₂COOR⁵⁵ and CH₂CH₂COOR⁵⁵ can be introduced bytreatment with the appropriate 2-halo acetic and, respectively, 3-halopropionic acid derivatives. Any other functionalization of diarylaminogroups known can be employed for introduction of substituents R⁴³.

[0984] iii: Cleavage of the methoxy groups of 199, conveniently bytreatment with excess boron tribromide in dichloromethane attemperatures ranging from about −20° to about room temperature.

[0985] iv: The intermediate bis-phenol derivative is preferably reactedwith R³⁹ and R⁴⁰—X′ (X′═OTf, Br, I) in the presence of strong bases suchas sodium hydride in tetrahydrofuran, dioxan or DMF in the presence of aphase transfer catalyst such as TDA-I. Any other functionalization forphenol groups can be employed for introduction of substituents R³⁹ andR⁴⁰.

[0986] v: The cyano group of 199 and, respectively, 200 is hydrolyzedunder acidic conditions, e.g. with 25% aqueous hydrochloric acid in asuitable solvent such as dioxane at an elevated temperature,conveniently at about 100° C.

[0987] vi: The phthalimide group is cleaved, conveniently byhydrazinolysis, e.g. with hydrazine hydrate in suitable solvent such asethanol.

[0988] vii: The free amino group is conveniently protected with reagentssuch as 9-fluorenylmethoxcarbonyl chloride or 9-fluorenylmethoxcarbonylsuccinimide using a base such as sodium carbonate or triethylamine insuitable solvent or mixture of solvents such as dioxane and water, ordichloromethane to yield 201 and, respectively, 202.

[0989] i: The cyano group of 199 is hydrolyzed, conveniently underacidic conditions, e.g. with 25% aqueous hydrochloric acid in a suitablesolvent such as dioxane at an elevated temperature, e.g. at about 100°C.

[0990] ii: The phthalimide group of the intermediate is cleaved,conveniently by hydrazinolysis, e.g. with hydrazine hydrate in asuitable solvent such as ethanol to yield 203.

[0991] iii: Double ortho-bromination of 203 is performed preferably withexcess bromine in acetic acid and dichloromethane. In a similar fashionR⁴¹═R⁴²═NO₂ can be introduced by treatment with HNO₃ in acetic acid andR⁴¹═R⁴²═CH₂—NPht by treatment with hydroxymethyl phthalimide in H₂SO₄.Any other fictionalization by electrophilic aromatic substitution can beemployed for introduction of substituents R⁴¹ and R⁴².

[0992] iv: The amino group is protected, conveniently Cbz-protected,with reagents such as benzyloxycarbonyl chloride or succinimide in asuitable solvent such as dioxane in the presence of a base such asaqueous sodium hydroxide.

[0993] v: The carboxylic acid group is esterified, preferably with DBUand methyl iodide in DMF to yield 204.

[0994] vi: Regioselective bromination of 203 is performed preferablywith bromine in acetic acid and dichloromethane. In a similar fashionR⁴¹═NO₂ can be introduced by treatment with HNO₃ in acetic acid andR⁴¹=CR₂—NPht by treatment with hydroxymethyl phthalimide in H₂SO₄.

[0995] vii: The amino group is conveniently Cbz-protected with reagentssuch as benzyloxycarbonyl chloride or succinimide in a suitable solventsuch as dioxane in presence of a base such as aqueous sodium hydroxide.

[0996] viii: The carboxylic acid group is esterified, preferably withDBU and methyl iodide in DMF to yield 205.

[0997] ix: Introduction of lower alkyl, substituted lower alkyl and arylsubstituents (41) for 205 and (R⁴¹ and R⁴²) for 204, conveniently bypalladium(0)-catalyzed Stille-(Stille, J. K. Angew. Chem. 1986, 68, 504)and Suzuki-couplings (Oh-e, T.; Mijaura, N.; Suzuki, A. J. Org. Chem.1993, 58, 2201). Any other functionalization known for aryl bromides canbe employed for introduction of substituents R⁴¹ and R⁴².

[0998] x: Removal of the Cbz-group, e.g. by hydrogenation using H₂ and acatalyst such as palladium on charcoal in a suitable solvent such asethanol, DMF and ethyl acetate.

[0999] xi: Hydrolysis of the ester group, conveniently under acidicconditions, e.g. with 25% aqueous hydrochloric acid in a suitablesolvent such as dioxane at an elevated temperature, preferably at about100° C.

[1000] xii: The intermediate free amino acid formed is convenientlyprotected with reagents such as 9-fluorenylmethoxcarbonyl chloride or9-fluorenylmethoxcarbonyl succinimide using a base such as sodiumcarbonate or triethylamine in a suitable solvent or mixture of solventssuch as dioxane and water, or dichloromethane to yield 206 and 207.

[1001] Templates(d) can be prepared according to D. Obrecht, U. Bohdal,C. Lehmann, P. Schönholzer, K. Müller, Tetrahedron 1995, 51, 10883; D.Obrecht, C. Abrecht, M. Altorfer, U. Bohdal, A. Grieder, M. Kleber, P.Pfyffer, K. Müller, Helv. Chim. Acta 1996, 79, 1315-1337.

[1002] Templates (e1) and (e2): See R. Mueller, L. Revesz, TetrahedronLett. 1994, 35, 4091; H.-G. Lubell, W. D. Lubell, J. Org. Chem. 1996,61, 9437; L. Colombo, M. DiGiacomo, G. Papeo, O. Carugo, C. Scolastico,L. Manzoni, Tetrahedron Lett. 1994, 35, 4031.

[1003] Templates (e3): See S. Hanessian, B. Ronan, A. Laoui, Bioorg.Med. Chem. Lett. 1994, 4, 1397.

[1004] Templates (e4): See S. Hanessian, G. McNaughton-Smith, Bioorg.Med. Chem. Lett. 1996, 6, 1567.

[1005] Templates (f): See T. P. Curran, P. M. McEnay, Tetrahedron Lett.1995, 36, 191-194.

[1006] Templates (g): See D. Gramberg, C. Weber, R. Beeli, J. Inglis, C.Bruns, J. A. Robinson, Helv. Chem. Acta 1995, 78, 1588-1606; K. H. Kim,J. P. Dumas, J. P. Germanas, J. Org. Chem. 1996, 61, 3138-3144.

[1007] Templates (h): See S. de Lombart, L. Blanchard, L. B. Stamford,D. M. Sperbeck, M. D. Grim, T. M. Jenson, H. R. Rodriguez, TetrahedronLett. 1994, 35, 7513-7516.

[1008] Templates (i1): See J. A. Robl, D. S. Karanewski, M. M. Asaad,Tetrahedron Lett. 1995, 5, 773-758.

[1009] Templates (i2): See T. P. Burkholder, T.-B. Le, E. L. Giroux, G.A. Flynn, Bioorg. Med. Chem. Lett. 1992, 2, 579.

[1010] Templates (i3) and (i4): See L. M. Simpkins, J. A. Robl, M. P.Cimarusti, D. E. Ryono, J. Stevenson, C.-Q. Sun, E. W. Petrillo, D. S.Karanewski, M. M. Asaad, J. E. Bird, T. R. Schaeffer, N.C. Trippodo,Abstracts of papers, 210^(th) Am. Chem. Soc Meeting, Chicago, Ill., MEDI064 (1995).

[1011] Templates (k): See D. BenIshai, A. R. McMurray, Tetrahedron 1993,49, 6399.

[1012] Templates (l): See E. G. von Roedern, H. Kessler, Angew. Chem.Int. Ed. Engl. 1994, 33, 687-689.

[1013] Templates (m): See R. Gonzalez-Muniz, M. J. Dominguez, M. T.Garcia-Lopez, Tetrahedron 1992, 48, 5191-5198.

[1014] Templates (n): See F. Esser, A. Carpy, H. Briem, H. Köppen, K.-H.Pook, Int. J. Pept. Res. 1995, 45, 540-546.

[1015] Templates (o): See N. De la Figuera, I. Alkorta, T. Garcia-Lopez,R. Herranz, R Gonzalez-Muniz, Tetrahedron 1995, 51, 7841.

[1016] Templates (p): See U. Slomcynska, D. K. Chalmers, F. Cornille, M.L. Smythe, D. D. Benson, K. D. Moeller, G. R. Marshall, J. Org. Chem.1996, 61, 1198-1204.

[1017] The β-hairpin peptidomimetics of the invention can be used in awide range of applications in order to inhibit the growth of or to killmicroorganisms and/or cancer cells.

[1018] They can be used for example as disinfectants or as preservativesfor materials such as foodstuffs, cosmetics, medicaments and othernutrient-containing materials or for preventing surfaces from microbialcolonization [J. M. Schierholz, C. Fleck, J. Beuth, G. Pulverer, J.Antimicrob. Chemother., 2000, 46, 45-50]. The β-hairpin peptidomimeticsof the invention can also be used to treat or prevent diseases relatedto microbial infection in plants and animals.

[1019] For use as disinfectants or preservatives the β-hairpinpeptidomimetics can be added to the desired material singly, as mixturesof several β-hairpin peptidomimetics or in combination with otherantimicrobial agents. The β-hairpin peptidomimetics may be administeredper se or may be applied as an appropriate formulation together withcarriers, diluents or excipients well known in the art, expediently in aform suitable for oral, topical, transdermal, injection, buccal,transmucosal, pulmonary or inhalation administration, such as tablets,dragees, capsules, solutions, liquids, gels, plasters, creams,ointments, syrups, slurries, suspensions, sprays, nebulisers orsuppositories.

[1020] When used to treat or prevent infections or diseases related tosuch infections or cancer, the β-hairpin peptidomimetics can beadministered singly, as mixtures of several β-hairpin peptidomimetics,in combination with other antimicrobial, antibiotic or anicancer agentsor in combination with other pharmaceutically active agents. Theβ-hairpin peptidomimetics can be administered per se or aspharmaceutical compositions.

[1021] Pharmaceutical compositions comprising β-hairpin peptidomimeticsof the invention may be manufactured by means of conventional mixing,dissolving, granulating, coated tablet-making, levigating, emulsifying,encapsulating, entrapping or lyophilizing processes. Pharmaceuticalcompositions may be formulated in conventional manner using one or morephysiologically acceptable carriers, diluents, excipients orauxilliaries which facilitate processing of the active β-hairpinpeptidomimetics into preparations which can be used pharmaceutically.Proper formulation depends upon the method of administration chosen.

[1022] For topical administration the β-hairpin peptidomimetics of theinvention may be formulated as solutions, gels, ointments, creams,suspensions, etc. as are well-known in the art.

[1023] Systemic formulations include those designed for administrationby injection, e.g. subcutaneous, intravenous, intramuscular, intrathecalor intraperitoneal injection, as well as those designed for transdermal,transmucosal, oral or pulmonary administration.

[1024] For injections, the β-hairpin peptidomimetics of the inventionmay be formulated in adequate solutions, preferably in physiologicallycompatible buffers such as Hink's solution, Ringer's solution, orphysiological saline buffer. The solution may contain formulatory agentssuch as suspending, stabilizing and/or dispersing agents. Alternatively,the β-hairpin peptidomimetics of the invention may be in powder form forcombination with a suitable vehicle, e.g., sterile pyrogen-free water,before use.

[1025] For transmucosal administration, penetrants appropriate to thebarrier to be permeated are used in the formulation as known in the art.

[1026] For oral administration, the compounds can be readily formulatedby combining the active β-hairpin peptidomimetics of the invention withpharmaceutically acceptable carriers well known in the art. Suchcarriers enable the β-hairpin peptidomimetics of the invention to beformulated as tablets, pills, dragees, capsules, liquids, gels, syrups,slurries, suspensions etc., for oral ingestion of a patient to betreated. For oral formulations such as, for example, powders, capsulesand tablets, suitable excipients include fillers such as sugars, such aslactose, sucrose, mannitol and sorbitol; cellulose preparations such asmaize starch, wheat starch, rice starch, potato starch, gelatin, gumtragacanth, methyl cellulose, hydroxypropylmethyl cellulose, sodiumcarboxymethylcellulose, and/or polyvinylpyrrolidone (PVP); granulatingagents; and binding agents. If desired, desintegrating agents may beadded, such as cross-linked polyvinylpyrrolidones, agar, or alginic acidor a salt thereof, such as sodium alginate. If desired, solid dosageforms may be sugar-coated or enteric-coated using standard techniques.

[1027] For oral liquid preparations such as, for example, suspensions,elixirs and solutions, suitable carriers, excipients or diluents includewater, glycols, oils, alcohols, etc. In addition, flavoring agents,preservatives, coloring agents and the like may be added.

[1028] For buccal administration, the composition may take the form oftablets, lozenges, etc. formulated as usual.

[1029] For administration by inhalation, the β-hairpin peptidomimeticsof the invention are conveniently delivered in form of an aeorosol sprayfrom pressurized packs or a nebulizer, with the use of a suitablepropellant, e.g. dichlorodifluoromethane, trichlorofluromethane, carbondioxide or another suitable gas. In the case of a pressurized aerosolthe dose unit may be determined by providing a valve to deliver ametered amount Capsules and cartridges of e.g. gelatin for use in aninhaler or insufflator may be formulated containing a powder mix of theβ-hairpin peptidomimetics of the invention and a suitable powder basesuch as lactose or starch.

[1030] The compounds may also be formulated in rectal or vaginalcompositions such as suppositories together with appropriate suppositorybases such as cocoa butter or other glycerides.

[1031] In addition to the formulation described previously, theβ-hairpin peptidomimetics of the invention may also be formulated asdepot preparations. Such long acting formulations may be administered byimplantation (e.g. subcutaneously or intramuscularly) or byintramuscular injection. For the manufacture of such depot preparationsthe β-hairpin peptidomimetics of the invention may be formulated withsuitable polymeric or hydrophobic materials (e.g. as an emulsion in anacceptable oil) or ion exchange resins, or as sparingly soluble salts.

[1032] In addition, other pharmaceutical delivery systems may beemployed such as liposomes and emulsions well known in the art. Certainorganic solvents such as dimethylsulfoxide also may be employed.Additionally, the β-hairpin peptidomimetics of the invention may bedelivered using a sustained-release system, such as semipermeablematrices of solid polymers containing the therapeutic agent. Varioussustained-release materials have been established and are well known bythose skilled in the art. Sustained-release capsules may, depending ontheir chemical nature, release the compounds for a few weeks up to over100 days. Depending on the chemical nature and the biological stabilityof the therapeutic agent, additional strategies for proteinstabilization may be employed.

[1033] As the β-hairpin pepdidomimetics of the invention may containcharged residues, they may be included in any of the above-describedformulations as free bases or as pharmaceutically acceptable salts.Pharmaceutically acceptable salts tend to be more soluble in aqueous andother protic solvents than are the corresponding free base forms.

[1034] The β-hairpin peptidomimetics of the invention, or compositionsthereof, will generally be used in an amount effective to achieve theintended purpose. It is to be understood that the amount used willdepend on a particular application.

[1035] For example, for use as a desinfectant or preservative, anantimicrobially effective amount of a β-hairpin peptidomimetic of theinvention, or a composition thereof, is applied or added to the materialto be desinfected or preserved. By antimicrobially effective amount ismeant an amount of a β-hairpin peptidomimetic of the invention orcomposition that inhibits the growth of, or is lethal to, a targetmicrobe population. While the antimicrobially effective amount willdepend on a particular application, for use as desinfectants orpreservatives the β-hairpin peptidomimetics of the invention, orcompositions thereof, are usually added or applied to the material to bedesinfected or preserved in relatively low amounts. Typically, theβ-hairpin peptidomimetics of the invention comprise less than about 5%by weight of a desinfectant solution or material to be preserved,preferably less than 1% by weight and more preferably less than 0.1% byweight. An ordinary skilled expert will be able to determineantimicrobially effective amounts of particular β-hairpinpepdidomimetics of the invention for particular applications withoutundue experimentation using, for example, the in vitro assays providedin the examples.

[1036] For use to treat or prevent microbial infections or diseasesrelated thereto and cancer, the β-hairpin pepidomimetics of theinvention, or compositions thereof, are administered or applied in atherapeutically effective amount. By therapeutically effective amount ismeant an amount effective in ameliorating the symptoms of, orameliorate, treat or prevent microbial infections or diseases relatedthereto. Determination of a therapeutically effective amount is wellwithin the capacities of those skilled in the art, especially in view ofthe detailed disclosure provided herein.

[1037] As in the case of desinfectants and preservatives, for topicaladministration to treat or prevent bacterial, yeast, fungal or otherinfections a therapeutically effective dose can be determined using, forexample, the in vitro assays provided in the examples. The treatment maybe applied while the infection is visible, or even when it is notvisible. An ordinary skilled expert will be able to determinetherapeutically effective amounts to treat topical infections withoutundue experimentation.

[1038] For systemic administration, a therapeutically effective dose canbe estimated initially from in vitro assays. For example, a dose can beformulated in animal models to achieve a circulating β-hairpinpeptidomimetic concentration range that includes the IC₅₀ as determinedin the cell culture (i.e. the concentration of a test compound that islethal to 50% of a cell culture), the MIC, as determined in cell culture(i.e. the concentration of a test compound that is lethal to 100% of acell culture). Such information can be used to more accurately determineuseful doses in humans.

[1039] Initial dosages can also be determined from in vivo data, e.g.animal models, using techniques that are well known in the art. Onehaving ordinary skills in the art could readily optimize administrationto humans based on animal data.

[1040] Dosage amount for applications as antimicrobial agents may beadjusted individually to provide plasma levels of the β-hairpinpeptidomimetics of the invention which are sufficient to maintain thetherapeutic effect. Usual patient dosages for administration byinjection range from about 0.1-5 mg/kg/day, preferably from about 0.5 to1 mg/kg/day. Therapeutically effective serum levels may be achieved byadministering multiple doses each day.

[1041] In cases of local administration or selective uptake, theeffective local concentration of the β-hairpin peptidomimetics of theinvention may not be related to plasma concentration. One having theskills in the art will be able to optimize therapeutically effectivelocal dosages without undue experimentation.

[1042] The amount of β-hairpin peptidomimetics administered will, ofcourse, be dependent on the subject being treated, on the subject'sweight, the severity of the affliction, the manner of administration andthe judgement of the prescribing physician.

[1043] The antimicrobial therapy may be repeated intermittently whileinfections are detectable or even when they are not detectable. Thetherapy may be provided alone or in combination with other drugs, suchas for example antibiotics or other antimicrobial agents.

[1044] Normally, a therapeutically effective dose of the β-hairpinpeptidomimetics described herein will provide therapeutic benefitwithout causing substantial toxicity.

[1045] Hemolysis of red blood cells is often employed for assessment oftoxicity of related compounds such as protegrin or tachyplesin. Valuesare given as %-lysis of red blood cells observed at a concentration of100 μg/ml. Typical values determined for cationic peptides such asprotegrin and tachyplesin range between 30-40% with average MIC-valuesof 1-5 μg/ml over a wide range of pathogens. Normally, β-hairpinpeptidomimetics of the invention will show hemolysis in a range of0.5-10%, often in a range of 1-5%, at activity levels comparable tothose mentioned above for protegrin and tachyplesin. Thus preferredcompounds exhibit low MIC-values and low %-hemolysis of red blood cellsobserved at a concentration of 100 μg/ml.

[1046] Toxicity of the β-hairpin peptidomimetics of the invention hereincan be determined by standard pharmaceutical procedures in cell culturesor experimental animals, e.g., by determining the LD₅₀ (the dose lethalto 50% of the population) or the LD₁₀₀ (the dose lethal to 100% of thepopulation). The dose ratio between toxic and therapeutic effect is thetherapeutic index. Compounds which exhibit high therapeutic indices arepreferred. The data obtained from these cell culture assays and animalstudies can be used in formulating a dosage range that is not toxic foruse in humans. The dosage of the β-hairpin peptidomimetics of theinvention lies preferably within a range of circulating concentrationsthat include the effective dose with little or no toxicity. The dosagemay vary within the range depending upon the dosage form employed andthe route of administration utilized. The exact formulation, route ofadministration and dose can be chosen by the individual physician inview of the patient's condition (see, e.g. Fingl et at. 1975, In: ThePharmacological Basis of Therapeutics, Ch.1, p.1).

[1047] The following Examples illustrate the invention in more detailbut are not intended to limit its scope in any way. The followingabbreviations are used in these Examples:

[1048] HBTU: 1-benzotriazol--yl-tetramethylurounium hexafluorophosphate(Knorr et al. Tetrahedron Lett. 1989, 30, 1927-1930)

[1049] HOBt: 1-hydroxybenzotriazole

[1050] DIEA: diisopropylethylamine

[1051] HOAT: 7-aza-1-hydroxybenzotriazole

[1052] HATU: O-7-aza-benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronoiumhexafluorophosphate Carpino et al. Tetrahedron Lett. 1994, 35,2279-2281)

EXAMPLES

[1053] 1. Peptide Synthesis

[1054] Coupling of the First Protected Amino Acid Residue

[1055] 0.5 g of 2-chlorotritylchloride resin (Barlos et al. TetrahedronLett. 1989, 30, 3943-3946) (0.83 mMol/g, 0.415 mmol) was filled into adried flask The resin was suspended in CH₂Cl₂ (2.5 ml) and allowed toswell at room temperature under constant stirring. The resin was treatedwith 0.415 mMol (1 eq) of the first suitably protected amino acidresidue (see below) and 284 μl (4eq) of diisopropylethylamine (IDEA) inCH₂Cl₂ (2.5 ml), the mixture was shaken at 25° C. for 15 minutes, pouredonto the pre-swollen resin and stirred at 25° C. for 18 hours. The resincolour changed to purple and the solution remained yellowish. The resinwas washed extensively (CH₂Cl₂/MeOH/DIEA: 17/2/1; CH₂Cl₂, DMF; CH₂Cl₂;Et₂O, 3 times each) and dried under vacuum for 6 hours.

[1056] Loading was typically 0.6-0.7 mMol/g.

[1057] The following preloaded resins were prepared:Fmoc-GlyO-chlorotritylresin; Fmoc-Arg(Pbf)O-chlorotritylresin;Fmoc-Lys(Boc)O-chlorotritylresin.

[1058] 1.1. Procedure 1

[1059] The synthesis was carried out using a Syro-peptide synthesizer(Multisyntech) using 24 to 96 reaction vessels. In each vessel wasplaced 60 mg (weight of the resin before loading) of the above resin.The following reaction cycles were programmed and carried out: StepReagent Time 1 CH₂Cl₂, wash and swell (manual)  3 × 1 min. 2 DMF, washand swell  1 × 5 min. 3 40% piperidine/DMF  1 × 5 min. 4 DMF, wash  5 ×2 min. 5 5 equiv. Fmoc amino acid/DMF + 1 × 120 min. 5 eq. HBTU + 5 eq.HOBt + 5 eq. DIEA 6 DMF, wash  4 × 2 min. 7 CH₂Cl₂, wash (at the end ofthe synthesis)  3 × 2 min.

[1060] Steps 3 to 6 are repeated to add each amino-acid.

[1061] Cleavage of the Fully Protected Peptide Fragment

[1062] After completion of the synthesis, the resin was suspended in 1ml (0.39 mMol) of 1% TFA in CH₂Cl₂ (v/v) for 3 minutes, filtered and thefiltrate was neutralized with 1 ml (1.17 mMol, 3eq.) of 20% DIEA inCH₂Cl₂ (v/v). This procedure was repeated twice to ensure completion ofthe cleavage. The filtrate was evaporated to dryness and the product wasfully deprotected to be analyzed by reverse phase-HPLC (column C₁₈) tomonitor the efficiency of the linear peptide synthesis.

[1063] Cyclization of the Linear Peptide

[1064] 100 mg of the fully protected linear peptide were dissolved inDMF (9 ml, conc. 10 mg/ml). Then 41.8 mg (0.110 mMol, 3 eq.) of HATU,14.9 mg (0.110 mMol, 3 eq) of HOAt and 1 ml (0.584 mMol) of 10% DIEA inDMF (v/v) were added and the mixture vortexed at 20° C. for 16 hours andsubsequently concentrated under high vacuum. The residue was partitionedbetween CH₂Cl₂ and H₂O/CH₃CN (90/10: v/v). The CH₂Cl₂ phase wasevaporated to yield the fully protected cyclic peptide.

[1065] Deprotection and Purification of the Cyclic Peptide:

[1066] The cyclic peptide obtained was dissolved in 1 ml of the cleavagemixture containing 95% trifluoroacetic acid (TFA), 2.5% water and 2.5%triisopropylsilane (TIS). The mixture was left to stand at 20° C. for2.5 hours and then concentrated under vacuum. The residue was dissolvedin a solution of H₂O/acetic acid (75/25: v/v) and the mixture extractedwith di-isopropylether.

[1067] The water phase was dried under vacuum and then the productpurified by preparative reverse phase HPLC.

[1068] After lyophilisation products were obtained as a white powder andanalysed by ESI-MS. The analytical data comprising HPLC retension timesand ESI-MS are shown in tables 1-7. Analytical HPLC retension times (RT,in minutes) were determined using a VYDAC 218TP104 (length 25 cm) columnwith gradient A: (10% CH₃CN+0.1% TFA and 90% H₂O+0.1% TFA to 98%CH₃CN+0.1% TFA and 2% H₂O+0.1% TFA in 20 minutes) and with gradient B:(10% CH₃CN+0.1% TFA and 90% H₂O+0.1% TFA to 98% CH₃CN+0.1% TFA and 2%H₂O+0.1% TFA in 21 minutes).

[1069] Examples ex.1-7 (n=8) are shown in table 1. The peptides weresynthesized starting with the amino acid at position P4 which wascoupled to the resin. Starting resins wereFmoc-Arg(Pbf)O-chlorotritylresin and Fmoc-Lys(Boc)O-chlorotritylresin,which were prepared as described above. The linear peptides weresynthesized on solid support according to procedure 1 in the followingsequence: P5-P6-P7-P8-^(D)Pro-P1-P2-P3-P4-resin, cleaved, cyclized,deprotected and purified as indicated. HPLC-retension times (minutes)were determined using gradient A.

[1070] Examples ex.831 (n=9) are shown in table 2. The peptides weresynthesized starting with the amino acid at position P5 which wascoupled to the resin. Starting resin wasFmoc-Arg(Pbf)O-chlorotritylresin, which was prepared as described above.The linear peptides were synthesized on solid support according toprocedure 1 in the following sequence:P6-P7-P8-P9-^(D)Pro-Pro-P1-P2-P3-P4-P5-resin, cleaved, cyclized,deprotected and purified as indicated. HPLC-retension times (minutes)were determined using gradient A.

[1071] Examples ex.32-58 (n=10) are shown in table 3. The peptides weresynthesized staring with the amino acid at position P5 which was coupledto the resin. Starting resin was Fmoc-Arg(Pbf)O-chlorotritykesin, whichwas prepared as described above. The linear peptides were synthesized onsolid support according to procedure 1 in the following sequence:P6-P7-P8-P9-P10-^(D)Pro-Pro-P1-P2-P3-P4-P5-resin, cleaved, cyclized,deprotected and purified as indicated. HPLC-retension times (minutes)were determined using gradient A.

[1072] Examples ex.59-70 (n=11) are shown in table 4. The peptides weresynthesized starting with the amino acid at position P5 which wascoupled to the resin. Starting resin wasFmoc-Arg(Pbf)O-chlorotritylresin, which was prepared as described above.The linear peptides were synthesized on solid support according toprocedure 1 in the following sequence:P6-P7-P8-P9-P10-P11-^(D)Pro-Pro-P1-P2-P3-P4-P5-resin, cleaved, cyclized,deprotected and purified as indicated. HPLC-retension times (minutes)were determined using gradient A.

[1073] Examples ex.71-84 (n=14) are shown in table 5. The peptides weresynthesized starting with the amino acid at position P7 which wascoupled to the resin. Starting resin wasFmoc-Arg(Pbf)O-chlorotritylresin, which was prepared as described above.The linear peptides were synthesized on solid support according toprocedure 1 in the following sequence:P8-P9-P10-P11-P12-P13-P14-^(D)Pro-P1-P2-P3-P4P5-P6-P7-resin, cleaved,cyclized, deprotected and purified as indicated. HPLC-retension times(minutes) were determined using gradient A.

[1074] Examples ex.85-95 (n=16) are shown in table 6. The peptides weresynthesized staring with the amino acid at position P8 which was coupledto the resin. Starting resins were Fmoc-Arg(Pbf)O-chlorotritylresin andFmoc-Lys(Boc)O-chlorotritylresin, which were prepared as describedabove. The linear peptides were synthesized on solid support accordingto procedure 1 in the following sequence:P9-P10-P11-P12-P13-P13-P15-P16-^(D)Pro-P1-P2-P3-P4P5-P6-P7-P8-resin,cleaved, cyclized, deprotected and purified as indicated. HPLC-retensiontimes (minutes) were determined using gradient A.

[1075] Examples ex.96-246, ex.276 (n=12) are shown in table 7. Thepeptides (exept ex.177 and ex.181) were synthesized starting with theamino acid at position P6 which was grafted to the resin. Startingresins were Fmoc-Arg(Pbf)O-chlorotritylresin andFmoc-Lys(Boc)O-chlorotritylresin, which were prepared as describedabove. The linear peptides were synthesized on solid support accordingto procedure 1 in the following sequence:P7-P8-P9-P10-P11-P12-^(D)Pro-Pro-P1-P2-P3-P4-P5-P6-resin, cleaved,cyclized, deprotected and purified as indicated. HPLC-retension times(minutes) were determined using gradient A.

[1076] Examples ex.177 to ex.181 (n=12) are shown in table 7. Thepeptides were synthesized starting with the amino acid at position P7which was coupled to the resin. Starting resin wasFmoc-Arg(Pbf)O-chlorotritylresin, which were prepared as describedabove. The linear peptides were synthesized on solid support accordingto procedure 1 in the following sequence:P8-P9-P10-P11-P12-^(D)Pro-Pro-P1-P2-P3-P4P5-P6-P7-resin, cleaved,cyclized, deprotected and purified as indicated HPLC-retension times(minutes) were determined using gradient A.

[1077] Examples ex.247-277 (n=12) are shown in table 7. The peptideswere synthesized starting with the amino acid at position P6 which wasgrafted to the resin. Starting resins wereFmoc-Arg(Pbf)O-chlorotritylesin and Fmoc-Lys(Boc)O-chlorotritylresin,which were prepared as described above. The linear peptides weresynthesized on solid support according to procedure 1 in the followingsequence: P7-P8-P9-P10-P11-P12-^(D)Pro-BB-P1-P2-P3-P4-P5-P6-resin,cleaved, cyclized, deprotected and purified as indicated. BB: Gly(ex.247); Arg(Pmc) (ex.248); Y(Bzl) (ex.249); Phe (ex250); Trp (ex.251);Leu (ex.252); Ile (ex.253); Cha (ex.254); 2-Nal (ex.255); 219a (ex.256);219b (ex.257); 219c (ex.258); 219d (ex.259); 219e (ex.260); 219f(ex.261); 219g (ex.262); 219h (ex.263); 219i (ex.264); 219k (ex.265);2191 (ex.266); 219m(ex267); 219n (ex.268); 219o (ex.269); 219p (ex.270);219q (ex.271); 219r (ex.272); 219s (ex.273); 219t (ex.274), 219u(ex.275). Building blocks 219a-u are described below.

[1078] Example ex.277 (n=12) is shown in table 7. The peptide wassynthesized starting with the amino acid at position P6 which wasgrafted to the resin. Starting resin wasFmoc-Arg(Pbf)O-chlorotritylresin, which were prepared as describedabove. The linear peptide was synthesized on solid support according toprocedure 1 in the following sequence:P7-P5-P9-P10-P11-P12-(c1-1)-P1-P2-P3-P4-P5-P6-resin, cleaved, cyclized,deprotected and purified as indicated.

[1079] Building block (c1-1) is described below.

[1080] Examples ex.278300 (n=12) are shown in table 7. The peptides weresynthesized starting with the amino acid at position P6 which wasgrafted to the resin. Starting resins wereFmoc-Arg(Pbf)O-chlorotritylresin, Fmoc-Tyr(Bzl)O-chlorotrityl resin andFmoc-)Tyr(Bzl)O-chlorotrityl resin which were prepared as describedabove. The linear peptide was synthesized on solid support according toprocedure 1 in the following sequence:P7-P8-P9-P10-P11-P12-^(D)Pro-Pro-P1-P2-P3-P4P5-P6-resin, cleaved,cyclized, deprotected and purified as indicated. AnalyticalHPLC-retention times (RT, in minutes) were determined using a VYDAC218TP104 (length 25 cm) column with gradient B (10% CH₃CN+0.1% TFA and90% H₂O+0.1% TFA to 98% CH₃CN+0.1% TFA and 2% H₂O+0.1% TFA in 21minutes).

[1081] Retention times (minutes) were the following: ex.278 (11.43);ex.279 (11.64); ex.280 (10.57); ex.281 (10.04); ex282 (10.63); ex.283(10.00); ex.284 (9.21).

[1082] Retention times (minutes) for examples 285-300 were determinedwith gradient C: VYDAC C₁₈-column (length 15 cm); (8% CH₃CN+0.1% TFA and92% H₂O+0.1% TFA to 62.8% CH₃CN+0.1% TFA and 37.2% H₂O+0.1% TFA in 8minutes to 100% CH₃CN+0.1% TFA in 9 minutes).

[1083] ex.285 (5.37; 5.57)*; ex.286 (5.17); ex.287 (5.0); ex.288(4.15;4.37)*; ex.289 (4.47; 4.72)*; ex.290 (3.45; 3.72)*; ex.291 (3.65;3.82)*; ex.292 (4.27); ex.293 (4.10); ex.294 (3.83; 4.13)*; ex.296(4.38; 4.67)*; ex.297 (4.10; 4.32)*; ex.298 (4.12); ex.299(4.47);ex.300(5.03). TABLE 1 Examples ex. 1-7 (n = 8) Example SEQ. ID P1 P2 P3P4 P5 P6 P7 P8 Template RT(′) %^(a)) MS 1. SEQ ID NO: 1 Tyr Val Arg ArgArg Phe Leu Val ^(D)Pro^(L)Pro 18.6 76 1284.6 2. SEQ ID NO: 2 Tyr ValArg Lys Gly Phe Leu Val ^(D)Pro^(L)Pro 18.8 86 1157.4 3. SEQ ID NO: 3Trp Val Arg Lys Gly Phe Leu Trp ^(D)Pro^(L)Pro 22.0 70 1263.8 4. SEQ IDNO: 4 Tyr Val Arg Arg Arg Trp Leu Val ^(D)Pro^(L)Pro 19.1 35 1323.6 5.SEQ ID NO: 5 Tyr Val Tyr Arg Arg Phe Leu Val ^(D)Pro^(L)Pro 20.7 811287.6 6. SEQ ID NO: 6 Lys Val Tyr Arg Arg Phe Leu Val ^(D)Pro^(L)Pro16.7 75 1256.6 7. SEQ ID NO: 7 Lys Val Tyr Lys Gly Phe Leu Trp^(D)Pro^(L)Pro 19.5 64 1216.5

[1084] TABLE 2 Examples ex. 8-29 (n = 9) Example SEQ. ID P1 P2 P3 P4 P5P6 P7 P8 P9 Template RT(′) %^(a)) MS 8. SEQ ID NO: 8 Arg Phe Leu Arg ArgArg Leu Phe Arg ^(D)Pro^(L)Pro 10.5 35 1495.9 9. SEQ ID NO: 9 Arg TyrLeu Arg Arg Arg Leu Tyr Arg ^(D)Pro^(L)Pro 8.8 46 1527.9 10. SEQ ID NO:10 Arg Phe Phe Arg Arg Arg Leu Phe Arg ^(D)Pro^(L)Pro 10.0 26 1529.9 11.SEQ ID NO: 11 Arg Tyr Tyr Arg Arg Arg Leu Tyr Arg ^(D)Pro^(L)Pro 8.0 901577.9 12. SEQ ID NO: 12 Leu Phe Phe Arg Arg Arg Leu Phe Arg^(D)Pro^(L)Pro 10.2 52 1502.9 13. SEQ ID NO: 13 Leu Tyr Tyr Arg Arg ArgLeu Tyr Arg ^(D)Pro^(L)Pro 8.4 30 1550.9 14. SEQ ID NO: 14 Arg Phe LeuPhe Arg Arg Leu Leu Arg ^(D)Pro^(L)Pro 10.1 51 1468.9 15. SEQ ID NO: 15Arg Tyr Leu Tyr Arg Arg Leu Leu Arg ^(D)Pro^(L)Pro 8.8 55 1500.9 16. SEQID NO: 16 Leu Phe Leu Phe Arg Arg Leu Phe Arg ^(D)Pro^(L)Pro 9.7 381459.9 17. SEQ ID NO: 17 Leu Tyr Leu Tyr Arg Arg Leu Tyr Arg^(D)Pro^(L)Pro 11.8 67 1507.9 18. SEQ ID NO: 18 Arg Phe Leu Phe Arg ArgLeu Phe Leu ^(D)Pro^(L)Pro 10.3 57 1459.9 19. SEQ ID NO: 19 Arg Tyr LeuTyr Arg Arg Leu Tyr Leu ^(D)Pro^(L)Pro 11.7 66 1507.9 20. SEQ ID NO: 20Phe Leu Leu Phe Arg Arg Leu Phe Arg ^(D)Pro^(L)Pro 9.9 67 1459.9 21. SEQID NO: 21 Tyr Leu Leu Tyr Arg Arg Leu Tyr Arg ^(D)Pro^(L)Pro 11.9 571507.9 22. SEQ ID NO: 22 Arg Leu Leu Phe Arg Arg Leu Phe Phe^(D)Pro^(L)Pro 10.1 68 1459.9 23. SEQ ID NO: 23 Arg Leu Leu Tyr Arg ArgLeu Tyr Tyr ^(D)Pro^(L)Pro 11.5 63 1507.9 24. SEQ ID NO: 24 Arg Phe LeuArg Arg Phe Leu Phe Arg ^(D)Pro^(L)Pro 8.5 33 1502.9 25. SEQ ID NO: 25Arg Phe Leu Arg Arg Phe Phe Leu Arg ^(D)Pro^(L)Pro 10.3 30 1502.9 26.SEQ ID NO: 26 Arg Tyr Leu Arg Arg Tyr Tyr Leu Arg ^(D)Pro^(L)Pro 12.6 651550.9 27. SEQ ID NO: 27 Leu Tyr Leu Arg Arg Tyr Leu Tyr Arg^(D)Pro^(L)Pro 10.1 29 1491.8 28. SEQ ID NO: 28 Leu Leu Phe Phe Arg ArgLeu Phe Arg ^(D)Pro^(L)Pro 12.1 35 1443.8 29. SEQ ID NO: 29 Leu Leu TyrTyr Arg Arg Leu Tyr Arg ^(D)Pro^(L)Pro 10.3 33 1491.8 30. SEQ ID NO: 30Arg Leu Phe Phe Arg Arg Leu Phe Leu ^(D)Pro^(L)Pro 12.1 35 1459.9 31.SEQ ID NO: 31 Arg Leu Tyr Tyr Arg Arg Leu Tyr Leu ^(D)Pro^(L)Pro 10.3 331507.8

[1085] TABLE 3 Examples ex. 32-58 (n = 10) Example Sequ. ID P1 P2 P3 P4P5 P6 P7 P8 P9 P10 Template RT(′) %^(a)) MS 32. SEQ ID NO: 32 Arg PheLeu Phe Arg Arg Arg Leu Phe Arg ^(D)Pro^(L)Pro 10.2 37 1643.0 33. SEQ IDNO: 33 Arg Tyr Leu Tyr Arg Arg Arg Leu Tyr Arg ^(D)Pro^(L)Pro 8.3 411691.0 34. SEQ ID NO: 34 Arg Phe Phe Phe Arg Arg Arg Leu Leu Arg^(D)Pro^(L)Pro 10.1 45 1643.0 35. SEQ ID NO: 35 Arg Tyr Tyr Tyr Arg ArgArg Leu Leu Arg ^(D)Pro^(L)Pro 8.87 70 1691.0 36. SEQ ID NO: 36 Arg LeuPhe Phe Arg Arg Arg Leu Phe Arg ^(D)Pro^(L)Pro 10.4 56 1643.0 37. SEQ IDNO: 37 Leu Tyr Leu Tyr Arg Arg Arg Leu Tyr Arg ^(D)Pro^(L)Pro 9.6 351648.0 38. SEQ ID NO: 38 Arg Phe Leu Phe Arg Arg Arg Leu Phe Leu^(D)Pro^(L)Pro 11.1 50 1600.0 39. SEQ ID NO: 39 Arg Tyr Leu Tyr Arg ArgArg Leu Tyr Leu ^(D)Pro^(L)Pro 9.81 41 1648.0 40. SEQ ID NO: 40 Leu LeuPhe Phe Arg Arg Arg Leu Phe Arg ^(D)Pro^(L)Pro 11.8 58 1600.0 41. SEQ IDNO: 41 Arg Leu Phe Phe Arg Arg Arg Leu Phe Leu ^(D)Pro^(L)Pro 11.6 541600.0 42. SEQ ID NO: 42 Leu Tyr Tyr Tyr Arg Arg Arg Leu Leu Arg^(D)Pro^(L)Pro 9.9 51 1648.0 43. SEQ ID NO: 43 Arg Phe Phe Phe Arg ArgArg Leu Leu Leu ^(D)Pro^(L)Pro 11.3 49 1600.0 44. SEQ ID NO: 44 Arg TyrTyr Tyr Arg Arg Arg Leu Leu Leu ^(D)Pro^(L)Pro 9.9 63 1648.0 45. SEQ IDNO: 45 Arg Leu Leu Phe Arg Gly Arg Phe Phe Arg ^(D)Pro^(L)Pro 10.6 781543.9 46. SEQ ID NO: 46 Arg Leu Leu Tyr Arg Gly Arg Tyr Tyr Arg^(D)Pro^(L)Pro 9.1 45 1591.9 47. SEQ ID NO: 47 Arg Phe Phe Phe Arg GlyArg Leu Leu Arg ^(D)Pro^(L)Pro 10.4 43 1543.9 48. SEQ ID NO: 48 Arg TyrTyr Tyr Arg Gly Arg Leu Leu Arg ^(D)Pro^(L)Pro 8.8 48 1591.9 49. SEQ IDNO: 49 Leu Phe Leu Phe Arg Gly Arg Leu Phe Arg ^(D)Pro^(L)Pro 12.4 651500.9 50. SEQ ID NO: 50 Leu Tyr Leu Tyr Arg Gly Arg Leu Tyr Arg^(D)Pro^(L)Pro 10.3 58 1548.9 51. SEQ ID NO: 51 Arg Phe Leu Phe Arg GlyArg Leu Phe Leu ^(D)Pro^(L)Pro 12.3 42 1500.9 52. SEQ ID NO: 52 Arg TyrLeu Tyr Arg Gly Arg Leu Tyr Leu ^(D)Pro^(L)Pro 10.6 20 1548.9 53. SEQ IDNO: 53 Leu Arg Phe Phe Arg Leu Arg Leu Phe Arg ^(D)Pro^(L)Pro 11.9 511600.0 54. SEQ ID NO: 54 Leu Arg Tyr Tyr Arg Leu Arg Leu Tyr Arg^(D)Pro^(L)Pro 9.9 50 1648.0 55. SEQ ID NO: 55 Leu Leu Phe Phe Arg GlyArg Leu Phe Arg ^(D)Pro^(L)Pro 12.5 50 1500.9 56. SEQ ID NO: 56 Leu LeuTyr Tyr Arg Gly Arg Leu Tyr Arg ^(D)Pro^(L)Pro 10.1 38 1548.9 57. SEQ IDNO: 57 Arg Phe Leu Phe Arg Gly Arg Phe Arg Leu ^(D)Pro^(L)Pro 11.3 571543.9 58. SEQ ID NO: 58 Arg Tyr Leu Tyr Arg Gly Arg Tyr Arg Leu^(D)Pro^(L)Pro 10.8 56 1591.9

[1086] TABLE 4 Examples ex. 59-70 (n = 11) Ex- am- ple SEQ. ID P1 P2 P3P4 P5 P6 P7 P8 P9 P10 P11 Template RT(′) % MS 59. SEQ ID NO: 59 Arg LeuPhe Leu Arg Arg Arg Phe Phe Arg Leu ^(D)Pro^(L)Pro 11.1 75 1756.2 60.SEQ ID NO: 60 Arg Leu Tyr Leu Arg Arg Arg Tyr Tyr Arg Leu ^(D)Pro^(L)Pro9.5 28 1804.2 61. SEQ ID NO: 61 Leu Leu Phe Leu Arg Arg Arg Phe Phe ArgArg ^(D)Pro^(L)Pro 10.8 65 1756.2 62. SEQ ID NO: 62 Arg Leu Phe Leu ArgArg Arg Leu Phe Arg Phe ^(D)Pro^(L)Pro 11.3 57 1756.2 63. SEQ ID NO: 63Phe Leu Phe Leu Arg Arg Arg Leu Phe Arg Arg ^(D)Pro^(L)Pro 11.1 761756.2 64. SEQ ID NO: 64 Tyr Leu Tyr Leu Arg Arg Arg Leu Tyr Arg Arg^(D)Pro^(L)Pro 9.5 70 1804.2 65. SEQ ID NO: 65 Arg Arg Phe Leu Arg GlyArg Phe Phe Leu Arg ^(D)Pro^(L)Pro 9.8 36 1700.1 66. SEQ ID NO: 66 LeuLeu Tyr Tyr Arg Arg Leu Tyr Tyr Arg Arg ^(D)Pro^(L)Pro 9.9 47 1811.2 67.SEQ ID NO: 67 Leu Tyr Leu Tyr Arg Arg Tyr Leu Tyr Arg Arg ^(D)Pro^(L)Pro9.9 47 1811.2 68. SEQ ID NO: 68 Arg Arg Phe Phe Arg Arg Leu Phe Phe LeuLeu ^(D)Pro^(L)Pro 12.4 46 1747.2 69. SEQ ID NO: 69 Arg Leu Tyr Tyr ArgArg Leu Tyr Tyr Arg Leu ^(D)Pro^(L)Pro 9.9 51 1811.2 70. SEQ ID NO: 70Arg Leu Phe Phe Arg Gly Arg Phe Phe Arg Leu ^(D)Pro^(L)Pro 10.5 261691.1

[1087] TABLE 5 Examples ex. 71-84 (n = 14) Example SEQ. ID P1 P2 P3 P4P5 P6 P7 P8 P9 P10 71. SEQ ID NO: 71 Arg Tyr Leu Leu Tyr Arg Arg Arg TyrLeu 72. SEQ ID NO: 72 Arg Leu Leu Tyr Tyr Arg Arg Arg Tyr Leu 73. SEQ IDNO: 73 Arg Leu Leu Leu Tyr Arg Arg Arg Tyr Leu 74. SEQ ID NO: 74 Arg PheLeu Phe Leu Arg Arg Arg Phe Phe 75. SEQ ID NO: 75 Arg Tyr Leu Tyr LeuArg Arg Arg Tyr Tyr 76. SEQ ID NO: 76 Arg Phe Leu Phe Leu Arg Arg ArgPhe Leu 77. SEQ ID NO: 77 Arg Tyr Leu Tyr Leu Arg Arg Arg Tyr Leu 78.SEQ ID NO: 78 Arg Arg Leu Leu Phe Arg Arg Arg Phe Leu 79. SEQ ID NO: 79Arg Arg Leu Leu Tyr Arg Arg Arg Tyr Leu 80. SEQ ID NO: 80 Arg Arg LeuTyr Tyr Arg Arg Arg Tyr Leu 81. SEQ ID NO: 81 Arg Arg Leu Leu Tyr ArgArg Arg Tyr Leu 82. SEQ ID NO: 82 Arg Arg Leu Phe Leu Arg Arg Arg PhePhe 83. SEQ ID NO: 83 Arg Arg Leu Tyr Leu Arg Arg Arg Tyr Tyr 84. SEQ IDNO: 84 Arg Arg Leu Tyr Leu Arg Arg Arg Tyr Leu Example SEQ. ID P11 P12P13 P14 Template RT(′) % MS 71. SEQ ID NO: 71 Leu Tyr Arg Arg^(D)Pro^(L)Pro 9.4 48 2236.7 72. SEQ ID NO: 72 Leu Tyr Arg Arg^(D)Pro^(L)Pro 9.4 29 2236.7 73. SEQ ID NO: 73 Tyr Tyr Arg Arg^(D)Pro^(L)Pro 9.4 50 2236.7 74. SEQ ID NO: 74 Leu Phe Arg Arg^(D)Pro^(L)Pro 10.9 78 2206.7 75. SEQ ID NO: 75 Leu Tyr Arg Arg^(D)Pro^(L)Pro 9.1 51 2286.7 76. SEQ ID NO: 76 Phe Leu Arg Arg^(D)Pro^(L)Pro 10.6 79 2172.7 77. SEQ ID NO: 77 Tyr Leu Arg Arg^(D)Pro^(L)Pro 9.1 53 2236.7 78. SEQ ID NO: 78 Leu Phe Phe Arg^(D)Pro^(L)Pro 11.0 42 2172.7 79. SEQ ID NO: 79 Leu Tyr Tyr Arg^(D)Pro^(L)Pro 9.4 91 2236.7 80. SEQ ID NO: 80 Leu Tyr Tyr Arg^(D)Pro^(L)Pro 9.3 72 2286.7 81. SEQ ID NO: 81 Tyr Tyr Leu Arg^(D)Pro^(L)Pro 9.5 65 2236.7 82. SEQ ID NO: 82 Leu Phe Phe Arg^(D)Pro^(L)Pro 11.1 34 2206.7 83. SEQ ID NO: 83 Leu Tyr Tyr Arg^(D)Pro^(L)Pro 9.3 89 2286.7 84. SEQ ID NO: 84 Tyr Leu Tyr Arg^(D)Pro^(L)Pro 9.3 47 2236.7

[1088] TABLE 6 Examples ex. 85-95 (n = 16) Example Sequ. ID P1 P2 P3 P4P5 P6 P7 P8 P9 P10 P11 85. SEQ ID NO: 85 Lys Arg Leu Lys Tyr Val Arg ArgArg Trp Leu 86. SEQ ID NO: 86 Lys Arg Leu Lys Tyr Val Arg Arg Gly TrpLeu 87. SEQ ID NO: 87 Lys Arg Leu Lys Tyr Trp Arg Arg Arg Trp Tyr 88.SEQ ID NO: 88 Lys Arg Leu Tyr Tyr Trp Arg Arg Arg Trp Tyr 89. SEQ ID NO:89 Lys Arg Leu Lys Tyr Trp Arg Arg Gly Trp Tyr 90. SEQ ID NO: 90 Lys ArgLeu Tyr Tyr Trp Arg Arg Gly Trp Tyr 91. SEQ ID NO: 91 Lys Arg Leu TyrTyr Trp Arg Arg Arg Trp Lys 92. SEQ ID NO: 92 Lys Arg Leu Lys Tyr TrpArg Arg Gly Trp Lys 93. SEQ ID NO: 93 Tyr Lys Leu Arg Leu Lys Tyr ArgArg Trp Lys 94. SEQ ID NO: 94 Tyr Lys Leu Gln Leu Lys Trp Arg Arg PheLys 95. SEQ ID NO: 95 Tyr Lys Leu Gln Leu Gln Lys Lys Gly Trp GlnExample Sequ. ID P12 P13 P14 P15 P16 Template RT(′) % MS 85. SEQ ID NO:85 Val Lys Val Leu Arg ^(D)Pro^(L)Pro 13.7 70 2346.0 86. SEQ ID NO: 86Val Lys Val Leu Arg ^(D)Pro^(L)Pro 13.9 38 2246.8 87. SEQ ID NO: 87 ValLys Val Leu Arg ^(D)Pro^(L)Pro 13.6 34 2483.1 88. SEQ ID NO: 88 Val PheVal Leu Arg ^(D)Pro^(L)Pro 14.3 35 2537.1 89. SEQ ID NO: 89 Val Lys ValLeu Arg ^(D)Pro^(L)Pro 13.7 27 2383.9 90. SEQ ID NO: 90 Val Phe Val LeuArg ^(D)Pro^(L)Pro 14.6 39 2437.9 91. SEQ ID NO: 91 Val Phe Val Leu Arg^(D)Pro^(L)Pro 13.9 22 2402.1 92. SEQ ID NO: 92 Val Lys Val Leu Arg^(D)Pro^(L)Pro 13.4 26 2348.9 93. SEQ ID NO: 93 Tyr Arg Val Lys Phe^(D)Pro^(L)Pro 12.5 34 2402.1 94. SEQ ID NO: 94 Tyr Gln Val Lys Phe^(D)Pro^(L)Pro 12.1 21 2348.9 95. SEQ ID NO: 95 Tyr Gln Val Lys Phe^(D)Pro^(L)Pro 11.1 84 2383.9

[1089] TABLE 7 Example Sequ. ID P1 P2 P3 P4 P5 P6 P7 P8 P9 P10 P11 P12Template RT(′) % MS Examples ex. 96-128 (n = 12); 96. SEQ ID NO: 96 LeuArg Leu Val Tyr Lys Gly Phe Leu Tyr Arg Val ^(D)Pro^(L)Pro 21.6 921703.1 97. SEQ ID NO: 97 Leu Arg Phe Val Tyr Lys Gly Phe Leu Tyr Arg Val^(D)Pro^(L)Pro 21.6 95 1737.1 98. SEQ ID NO: 98 Leu Arg Thr Val Tyr LysGly Phe Leu Tyr Arg Val ^(D)Pro^(L)Pro 20.0 93 1691.1 99. SEQ ID NO: 99Leu Arg Lys Val Arg Lys Gly Arg Leu Tyr Arg Val ^(D)Pro^(L)Pro 15.7 991720.2 100. SEQ ID NO: 100 Leu Arg Lys Trp Tyr Lys Gly Phe Trp Tyr ArgVal ^(D)Pro^(L)Pro 17.6 60 1878.3 101. SEQ ID NO: 101 Leu Arg Lys ValTyr Arg Gly Phe Leu Tyr Arg Val ^(D)Pro^(L)Pro 17.8 61 1845.3 102. SEQID NO: 102 Leu Lys Lys Val Tyr Arg Arg Phe Leu Lys Lys Val^(D)Pro^(L)Pro 15.9 59 1754.3 103. SEQ ID NO: 103 Leu Arg Leu Lys TyrArg Arg Phe Lys Tyr Arg Val ^(D)Pro^(L)Pro 20.5 36 1874.3 104. SEQ IDNO: 104 Leu Arg Leu Glu Tyr Arg Arg Phe Glu Tyr Arg Val ^(D)Pro^(L)Pro21.5 99 1876.2 105. SEQ ID NO: 105 Leu Arg Leu Gln Tyr Arg Arg Phe GlnTyr Arg Val ^(D)Pro^(L)Pro 21.5 58 1874.2 106. SEQ ID NO: 106 Leu ArgLeu Lys Lys Arg Arg Trp Lys Tyr Arg Val ^(D)Pro^(L)Pro 18.1 51 1879.7107. SEQ ID NO: 107 Leu Arg Leu Lys Trp Arg Arg Lys Lys Tyr Arg Val^(D)Pro^(L)Pro 20.2 28 1879.7 108. SEQ ID NO: 108 Leu Arg Trp Lys TyrArg Arg Phe Lys Tyr Arg Val ^(D)Pro^(L)Pro 20.9 40 1948.7 109. SEQ IDNO: 109 Lys Val Arg Phe Arg Arg Arg Lys Leu Lys Leu Arg ^(D)Pro^(L)Pro15.7 75 1833.7 110. SEQ ID NO: 110 Leu Arg Leu Gln Tyr Arg Arg Trp GlnTyr Arg Val ^(D)Pro^(L)Pro 21.9 30 1913.3 111. SEQ ID NO: 111 Leu ArgLeu Gln Trp Arg Arg Phe Gln Tyr Arg Val ^(D)Pro^(L)Pro 22.6 75 1897.3112. SEQ ID NO: 112 Leu Arg Leu Gln Lys Arg Arg Trp Gln Tyr Arg Val^(D)Pro^(L)Pro 18.9 49 1878.3 113. SEQ ID NO: 113 Leu Arg Leu Gln TrpArg Arg Lys Gln Tyr Arg Val ^(D)Pro^(L)Pro 21.2 75 1878.3 114. SEQ IDNO: 114 Phe Arg Leu Gln Tyr Arg Arg Phe Gln Tyr Arg Val ^(D)Pro^(L)Pro22.3 50 1908.3 115. SEQ ID NO: 115 Leu Arg Leu Gln Tyr Arg Arg Phe GlnTyr Arg Phe ^(D)Pro^(L)Pro 22.4 99 1908.3 116. SEQ ID NO: 116 Phe ArgLeu Gln Tyr Arg Arg Phe Gln Tyr Arg Phe ^(D)Pro^(L)Pro 22.9 99 1956.3117. SEQ ID NO: 117 Leu Arg Leu Gln Tyr Arg Arg Phe Gln Trp Arg Val^(D)Pro^(L)Pro 22.7 15 1897.3 118. SEQ ID NO: 118 Leu Arg Trp Gln TyrArg Arg Phe Gln Tyr Arg Val ^(D)Pro^(L)Pro 21.9 21 1947.3 119. SEQ IDNO: 119 Gln Val Arg Phe Arg Arg Arg Lys Leu Gln Leu Arg ^(D)Pro^(L)Pro17.2 46 1831.3 120. SEQ ID NO: 120 Phe Arg Leu Lys Lys Arg Arg Trp LysTyr Arg Val ^(D)Pro^(L)Pro 10.5 52 1912.4 121. SEQ ID NO: 121 Cha ArgLeu Lys Lys Arg Arg Trp Lys Tyr Arg Val ^(D)Pro^(L)Pro 10.6 36 1918.4122. SEQ ID NO: 122 hPhe Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val^(D)Pro^(L)Pro 9.6 95 1926.4 123. SEQ ID NO: 123 2Nal Arg Leu Lys LysArg Arg Trp Lys Tyr Arg Val ^(D)Pro^(L)Pro 9.6 69 1962.4 124. SEQ ID NO:124 1Nal Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val ^(D)Pro^(L)Pro 11.847 1962.4 125. SEQ ID NO: 125 Nle Arg Leu Lys Lys Arg Arg Trp Lys TyrArg Val ^(D)Pro^(L)Pro 10.3 63 1878.4 126. SEQ ID NO: 126 Leu Arg PheLys Lys Arg Arg Trp Lys Tyr Arg Val ^(D)Pro^(L)Pro 10.6 44 1912.4 127.SEQ ID NO: 127 Leu Arg Cha Lys Lys Arg Arg Trp Lys Tyr Arg Val^(D)Pro^(L)Pro 10.8 41 1918.4 128. SEQ ID NO: 128 Leu Arg Y(bzl) Lys LysArg Arg Trp Lys Tyr Arg Val ^(D)Pro^(L)Pro 11.5 23 2018.5 Examples ex.129-161 (n = 12) 129. SEQ ID NO: 129 Leu Arg Trp Lys Lys Arg Arg Trp LysTyr Arg Val ^(D)Pro^(L)Pro 10.5 41 1951.4 130. SEQ ID NO: 130 Leu ArghPhe Lys Lys Arg Arg Trp Lys Tyr Arg Val ^(D)Pro^(L)Pro 10.6 32 1926.4131. SEQ ID NO: 131 Leu Arg 2Nal Lys Lys Arg Arg Trp Lys Tyr Arg Val^(D)Pro^(L)Pro 11.0 42 1962.4 132. SEQ ID NO: 132 Leu Arg 1Nal Lys LysArg Arg Trp Lys Tyr Arg Val ^(D)Pro^(L)Pro 10.9 43 1962.4 133. SEQ IDNO: 133 Leu Arg Val Lys Lys Arg Arg Trp Lys Tyr Arg Val ^(D)Pro^(L)Pro10.0 47 1864.3 134. SEQ ID NO: 134 Leu Arg Ile Lys Lys Arg Arg Trp LysTyr Arg Val ^(D)Pro^(L)Pro 10.3 34 1878.4 135. SEQ ID NO: 135 Leu ArgNle Lys Lys Arg Arg Trp Lys Tyr Arg Val ^(D)Pro^(L)Pro 10.3 90 1878.4136. SEQ ID NO: 136 Leu Arg Leu Lys Lys Arg Arg Tyr Lys Tyr Arg Val^(D)Pro^(L)Pro 9.9 48 1855.3 137. SEQ ID NO: 137 Leu Arg Leu Lys Lys ArgArg Y(Bzl) Lys Tyr Arg Val ^(D)Pro^(L)Pro 11.0 33 1945.4 138. SEQ ID NO:138 Leu Arg Leu Lys Lys Arg Arg hPhe Lys Tyr Arg Val ^(D)Pro^(L)Pro 10.352 1853.3 139. SEQ ID NO: 139 Leu Arg Leu Lys Lys Arg Arg 2Nal Lys TyrArg Val ^(D)Pro^(L)Pro 10.5 53 1889.4 140. SEQ ID NO: 140 Leu Arg LeuLys Lys Arg Arg 1Nal Lys Tyr Arg Val ^(D)Pro^(L)Pro 10.5 34 1889.4 141.SEQ ID NO: 141 Leu Arg Leu Lys Lys Arg Arg Val Lys Tyr Arg Val^(D)Pro^(L)Pro 9.9 49 1889.4 142. SEQ ID NO: 142 Leu Arg Leu Lys Lys ArgArg Ile Lys Tyr Arg Val ^(D)Pro^(L)Pro 10.0 32 1791.3 143. SEQ ID NO:143 Leu Arg Leu Lys Lys Arg Arg Leu Lys Tyr Arg Val ^(D)Pro^(L)Pro 10.146 1805.3 144. SEQ ID NO: 144 Leu Arg Leu Lys Lys Arg Arg Nle Lys TyrArg Val ^(D)Pro^(L)Pro 10.1 43 1805.3 145. SEQ ID NO: 145 Leu Arg LeuLys Lys Arg Arg His Lys Tyr Arg Val ^(D)Pro^(L)Pro 9.8 56 1829.3 146.SEQ ID NO: 146 Leu Arg Leu Lys Lys Arg Arg Trp Lys Phe Arg Val^(D)Pro^(L)Pro 10.9 45 1862.3 147. SEQ ID NO: 147 Leu Arg Leu Lys LysArg Arg Trp Lys Y(Bzl) Arg Val ^(D)Pro^(L)Pro 11.4 15 1968.5 148. SEQ IDNO: 148 Leu Arg Leu Lys Lys Arg Arg Trp Lys Trp Arg Val ^(D)Pro^(L)Pro10.8 56 1901.4 149. SEQ ID NO: 149 Leu Arg Leu Lys Lys Arg Arg Trp LyshPhe Arg Val ^(D)Pro^(L)Pro 11.3 32 1876.4 150. SEQ ID NO: 150 Leu ArgLeu Lys Lys Arg Arg Trp Lys 1Nal Arg Val ^(D)Pro^(L)Pro 11.6 24 1912.4151. SEQ ID NO: 151 Leu Arg Leu Lys Lys Arg Arg Trp Lys Val Arg Val^(D)Pro^(L)Pro 10.6 48 1814.3 152. SEQ ID NO: 152 Leu Arg Leu Lys LysArg Arg Trp Lys Ile Arg Val ^(D)Pro^(L)Pro 10.9 40 1828.3 153. SEQ IDNO: 153 Leu Arg Leu Lys Lys Arg Arg Trp Lys Leu Arg Val ^(D)Pro^(L)Pro10.7 18 1828.3 154. SEQ ID NO: 154 Leu Arg Leu Lys Lys Arg Arg Trp LysNle Arg Val ^(D)Pro^(L)Pro 11.2 40 1828.3 155. SEQ ID NO: 155 Leu ArgLeu Lys Lys Arg Arg Trp Lys Tyr Arg Phe ^(D)Pro^(L)Pro 10.6 35 1926.4156. SEQ ID NO: 156 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Cha^(D)Pro^(L)Pro 11.2 60 1932.5 157. SEQ ID NO: 157 Leu Arg Leu Lys LysArg Arg Trp Lys Tyr Arg Y(Bzl) ^(D)Pro^(L)Pro 11.7 37 2032.5 158. SEQ IDNO: 158 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Trp ^(D)Pro^(L)Pro10.4 69 1965.4 159. SEQ ID NO: 159 Leu Arg Leu Lys Lys Arg Arg Trp LysTyr Arg hPhe ^(D)Pro^(L)Pro 10.8 95 1940.4 160. SEQ ID NO: 160 Leu ArgLeu Lys Lys Arg Arg Trp Lys Tyr Arg 2Nal ^(D)Pro^(L)Pro 11.2 30 1976.5161. SEQ ID NO: 161 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg 1Nal^(D)Pro^(L)Pro 11.3 89 1976.5 Examples ex. 162-194 (n = 12) 162. SEQ IDNO: 162 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Ile ^(D)Pro^(L)Pro10.5 56 1892.4 163. SEQ ID NO: 163 Leu Arg Leu Lys Lys Arg Arg Trp LysTyr Arg Nle ^(D)Pro^(L)Pro 10.5 91 1892.4 164. SEQ ID NO: 164 Leu ArgLeu Lys Lys Arg Arg Trp Lys Tyr Arg His ^(D)Pro^(L)Pro 8.6 88 1916.4165. SEQ ID NO: 165 Leu Trp Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val^(D)Pro^(L)Pro 10.4 55 1908.4 166. SEQ ID NO: 166 Leu Leu Leu Lys LysArg Arg Trp Lys Tyr Arg Val ^(D)Pro^(L)Pro 10.6 88 1835.3 167. SEQ IDNO: 167 Leu Thr Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val ^(D)Pro^(L)Pro10.4 94 1823.3 168. SEQ ID NO: 168 Leu Gln Leu Lys Lys Arg Arg Trp LysTyr Arg Val ^(D)Pro^(L)Pro 10.4 55 1850.3 169. SEQ ID NO: 169 Leu ArgLeu Leu Lys Arg Arg Trp Lys Tyr Arg Val ^(D)Pro^(L)Pro 10.9 62 1863.3170. SEQ ID NO: 170 Leu Arg Leu Arg Lys Arg Arg Trp Lys Tyr Arg Val^(D)Pro^(L)Pro 10.3 45 1906.4 171. SEQ ID NO: 171 Leu Arg Leu Thr LysArg Arg Trp Lys Tyr Arg Val ^(D)Pro^(L)Pro 10.4 94 1851.3 172. SEQ IDNO: 172 Leu Arg Leu Gln Lys Arg Arg Trp Lys Tyr Arg Val ^(D)Pro^(L)Pro10.3 76 1878.3 173. SEQ ID NO: 173 Leu Arg Leu Lys Leu Arg Arg Trp LysTyr Arg Val ^(D)Pro^(L)Pro 11.9 43 1863.3 174. SEQ ID NO: 174 Leu ArgLeu Lys His Arg Arg Trp Lys Tyr Arg Val ^(D)Pro^(L)Pro 10.5 53 1887.3175. SEQ ID NO: 175 Leu Arg Leu Lys Arg Arg Arg Trp Lys Tyr Arg Val^(D)Pro^(L)Pro 10.4 37 1906.4 176. SEQ ID NO: 176 Leu Arg Leu Lys ThrArg Arg Trp Lys Tyr Arg Val ^(D)Pro^(L)Pro 11.4 45 1851.3 177. SEQ IDNO: 177 Leu Arg Leu Lys Lys Leu Arg Trp Lys Tyr Arg Val ^(D)Pro^(L)Pro10.8 58 1835.3 178. SEQ ID NO: 178 Leu Arg Leu Lys Lys His Arg Trp LysTyr Arg Val ^(D)Pro^(L)Pro 10.2 46 1859.3 179. SEQ ID NO: 179 Leu ArgLeu Lys Lys Lys Arg Trp Lys Tyr Arg Val ^(D)Pro^(L)Pro 10.3 53 1850.3180. SEQ ID NO: 180 Leu Arg Leu Lys Lys Thr Arg Trp Lys Tyr Arg Val^(D)Pro^(L)Pro 10.4 82 1823.3 181. SEQ ID NO: 181 Leu Arg Leu Lys LysGln Arg Trp Lys Tyr Arg Val ^(D)Pro^(L)Pro 10.4 36 1850.3 182. SEQ IDNO: 182 Leu Arg Leu Lys Lys Arg Trp Trp Lys Tyr Arg Val ^(D)Pro^(L)Pro10.8 70 1908.4 183. SEQ ID NO: 183 Leu Arg Leu Lys Lys Arg His Trp LysTyr Arg Val ^(D)Pro^(L)Pro 10.3 74 1859.3 184. SEQ ID NO: 184 Leu ArgLeu Lys Lys Arg Lys Trp Lys Tyr Arg Val ^(D)Pro^(L)Pro 10.2 50 1850.3185. SEQ ID NO: 185 Bip Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val^(D)Pro^(L)Pro 11.4 39 1988.5 186. SEQ ID NO: 186 4ClPhe Arg Leu Lys LysArg Arg Trp Lys Tyr Arg Val ^(D)Pro^(L)Pro 11.1 53 1946.8 187. SEQ IDNO: 187 AmPhe Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val ^(D)Pro^(L)Pro8.6 83 1927.4 188. SEQ ID NO: 188 S(Bzl) Arg Leu Lys Lys Arg Arg Trp LysTyr Arg Val ^(D)Pro^(L)Pro 10.4 66 1942.4 189. SEQ ID NO: 189 T(Bzl) ArgLeu Lys Lys Arg Arg Trp Lys Tyr Arg Val ^(D)Pro^(L)Pro 10.8 51 1956.4190. SEQ ID NO: 190 Orn Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val^(D)Pro^(L)Pro 8.4 84 1879.3 191. SEQ ID NO: 191 Leu Arg Bip Lys Lys ArgArg Trp Lys Tyr Arg Val ^(D)Pro^(L)Pro 11.3 39 1988.5 192. SEQ ID NO:192 Leu Arg 4ClPhe Lys Lys Arg Arg Trp Lys Tyr Arg Val ^(D)Pro^(L)Pro10.9 50 1946.8 193. SEQ ID NO: 193 Leu Arg AmPhe Lys Lys Arg Arg Trp LysTyr Arg Val ^(D)Pro^(L)Pro 9.2 82 1927.4 194. SEQ ID NO: 194 Leu ArgS(Bzl) Lys Lys Arg Arg Trp Lys Tyr Arg Val ^(D)Pro^(L)Pro 10.7 80 1942.4Examples ex. 195-227 (n = 12) 195. SEQ ID NO: 195 Leu Arg T(Bzl) Lys LysArg Arg Trp Lys Tyr Arg Val ^(D)Pro^(L)Pro 10.7 37 1956.4 196. SEQ IDNO: 196 Leu Arg Orn Lys Lys Arg Arg Trp Lys Tyr Arg Val ^(D)Pro^(L)Pro9.2 48 1879.3 197. SEQ ID NO: 197 Leu Arg Leu Lys Lys Arg Arg Bip LysTyr Arg Val ^(D)Pro^(L)Pro 10.8 57 1915.4 198. SEQ ID NO: 198 Leu ArgLeu Lys Lys Arg Arg 4ClPhe Lys Tyr Arg Val ^(D)Pro^(L)Pro 10.4 49 1873.8199. SEQ ID NO: 199 Leu Arg Leu Lys Lys Arg Arg AmPhe Lys Tyr Arg Val^(D)Pro^(L)Pro 9.8 43 1854.3 200. SEQ ID NO: 200 Leu Arg Leu Lys Lys ArgArg S(Bzl) Lys Tyr Arg Val ^(D)Pro^(L)Pro 10.3 48 1869.3 201. SEQ ID NO:201 Leu Arg Leu Lys Lys Arg Arg T(Bzl) Lys Tyr Arg Val ^(D)Pro^(L)Pro10.2 87 1883.4 202. SEQ ID NO: 202 Leu Arg Leu Lys Lys Arg Arg Orn LysTyr Arg Val ^(D)Pro^(L)Pro 9.7 31 1806.3 203. SEQ ID NO: 203 Leu Arg LeuLys Lys Arg Arg Trp Lys Bip Arg Val ^(D)Pro^(L)Pro 11.6 46 1938.5 204.SEQ ID NO: 204 Leu Arg Leu Lys Lys Arg Arg Trp Lys 4ClPhe Arg Val^(D)Pro^(L)Pro 11.21 48 1896.8 205. SEQ ID NO: 205 Leu Arg Leu Lys LysArg Arg Trp Lys S(Bzl) Arg Val ^(D)Pro^(L)Pro 11.5 32 1892.4 206. SEQ IDNO: 206 Leu Arg Leu Lys Lys Arg Arg Trp Lys T(Bzl) Arg Val^(D)Pro^(L)Pro 11.5 36 1906.4 207. SEQ ID NO: 207 Leu Arg Leu Lys LysArg Arg Trp Lys Orn Arg Val ^(D)Pro^(L)Pro 9.4 49 1829.3 208. SEQ ID NO:208 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Bip ^(D)Pro^(L)Pro 11.737 2002.5 209. SEQ ID NO: 209 Leu Arg Leu Lys Lys Arg Arg Trp Lys TyrArg 4ClPhe ^(D)Pro^(L)Pro 11.0 32 1960.8 210. SEQ ID NO: 210 Leu Arg LeuLys Lys Arg Arg Trp Lys Tyr Arg AmPhe ^(D)Pro^(L)Pro 8.6 88 1941.4 211.SEQ ID NO: 211 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg T(Bzl)^(D)Pro^(L)Pro 10.9 51 1970.5 212. SEQ ID NO: 212 Leu Arg Leu Lys LysArg Arg Trp Lys Tyr Arg Orn ^(D)Pro^(L)Pro 8.3 75 1893.4 213. SEQ ID NO:213 Leu Orn Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val ^(D)Pro^(L)Pro 10.363 1836.3 214. SEQ ID NO: 214 Leu Arg Leu Orn Lys Arg Arg Trp Lys TyrArg Val ^(D)Pro^(L)Pro 10.4 44 1864.3 215. SEQ ID NO: 215 Leu Arg LeuLys Orn Arg Arg Trp Lys Tyr Arg Val ^(D)Pro^(L)Pro 10.2 44 1864.3 216.SEQ ID NO: 216 Leu Arg Leu Lys Lys Arg Orn Trp Lys Tyr Arg Val^(D)Pro^(L)Pro 10.2 44 1836.3 217. SEQ ID NO: 217 Leu Arg Leu Lys LysArg Arg Trp Orn Tyr Arg Val ^(D)Pro^(L)Pro 10.3 40 1864.3 218. SEQ IDNO: 218 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Orn Val ^(D)Pro^(L)Pro10.2 92 1836.3 219. SEQ ID NO: 219 Leu Arg Leu Lys Lys Arg Gln Trp LysTyr Arg Val ^(D)Pro^(L)Pro 10.4 92 1850.3 220. SEQ ID NO: 220 Leu ArgLeu Lys Lys Arg Arg Trp Tyr Tyr Arg Val ^(D)Pro^(L)Pro 10.5 88 1913.4221. SEQ ID NO: 221 Leu Arg Leu Lys Lys Arg Arg Trp His Tyr Arg Val^(D)Pro^(L)Pro 10.4 49 1887.3 222. SEQ ID NO: 222 Leu Arg Leu Lys LysArg Arg Trp Arg Tyr Arg Val ^(D)Pro^(L)Pro 10.3 53 1906.4 223. SEQ IDNO: 223 Leu Arg Leu Lys Lys Arg Arg Trp Thr Tyr Arg Val ^(D)Pro^(L)Pro10.5 84 1851.3 224. SEQ ID NO: 224 Leu Arg Leu Lys Lys Arg Arg Trp GlnTyr Arg Val ^(D)Pro^(L)Pro 10.5 52 1878.3 225. SEQ ID NO: 225 Leu ArgLeu Lys Lys Arg Arg Trp Lys Tyr Tyr Val ^(D)Pro^(L)Pro 10.6 54 1885.3226. SEQ ID NO: 226 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Trp Val^(D)Pro^(L)Pro 10.9 47 1908.4 227. SEQ ID NO: 227 Leu Arg Leu Lys LysArg Arg Bip Lys Bip Arg Val ^(D)Pro^(L)Pro 12.3 50 1975.5 Examples ex.228-255 (n = 12) 228. SEQ ID NO: 228 Leu Arg Leu Arg Lys Arg Arg Bip LysTyr Arg Val ^(D)Pro^(L)Pro 10.9 46 1943.4 229. SEQ ID NO: 229 Leu ArgLeu Lys Lys Arg Arg Bip Arg Tyr Arg Val ^(D)Pro^(L)Pro 10.9 41 1943.4230. SEQ ID NO: 230 Leu Trp Leu Lys Lys Arg Arg Bip Lys Tyr Arg Val^(D)Pro^(L)Pro 11.0 73 1945.4 231. SEQ ID NO: 231 Leu Trp Leu Arg LysArg Arg Bip Lys Tyr Arg Val ^(D)Pro^(L)Pro 11.0 71 1973.5 232. SEQ IDNO: 232 Leu Trp Leu Lys Lys Arg Arg Bip Arg Tyr Arg Val ^(D)Pro^(L)Pro11.0 71 1973.5 233. SEQ ID NO: 233 Leu Trp Leu Arg Lys Arg Arg Bip LysBip Arg Val ^(D)Pro^(L)Pro 12.4 60 2033.6 234. SEQ ID NO: 234 Leu TrpLeu Lys Lys Arg Arg Bip Arg Bip Arg Val ^(D)Pro^(L)Pro 12.4 85 2033.6235. SEQ ID NO: 235 Leu Trp Leu Arg Lys Arg Arg Bip Arg Bip Arg Bip^(D)Pro^(L)Pro 11.6 50 2185.7 236. SEQ ID NO: 236 4ClPhe Arg Leu Lys LysArg Arg Bip Lys Tyr Arg Val ^(D)Pro^(L)Pro 10.7 39 1983.9 237. SEQ IDNO: 237 4ClPhe Arg Leu Lys Lys Arg Arg Bip Lys Bip Arg Val^(D)Pro^(L)Pro 13.0 36 2043.9 238. SEQ ID NO: 238 4ClPhe Arg Leu Lys LysArg Arg Bip Lys Tyr Arg Bip ^(D)Pro^(L)Pro 12.9 52 2108.0 239. SEQ IDNO: 239 4ClPhe Arg Leu Lys Lys Arg Arg Bip Lys Bip Arg Bip^(D)Pro^(L)Pro 12.6 68 2168.1 240. SEQ ID NO: 240 4ClPhe Arg Leu Arg LysArg Arg Bip Lys Tyr Arg Val ^(D)Pro^(L)Pro 11.7 46 2011.9 241. SEQ IDNO: 241 4ClPhe Arg Leu Lys Lys Arg Arg Bip Arg Tyr Arg Val^(D)Pro^(L)Pro 11.7 41 2011.9 242. SEQ ID NO: 242 4ClPhe Trp Leu Lys LysArg Arg Bip Lys Tyr Arg Val ^(D)Pro^(L)Pro 11.8 48 2013.9 243. SEQ IDNO: 243 4ClPhe Trp Leu Arg Lys Arg Arg Bip Lys Tyr Arg Val^(D)Pro^(L)Pro 11.9 38 2041.9 244. SEQ ID NO: 244 4ClPhe Trp Leu Lys LysArg Arg Bip Arg Tyr Arg Val ^(D)Pro^(L)Pro 11.9 74 2041.9 245. SEQ IDNO: 245 4ClPhe Trp Leu Arg Lys Arg Arg Bip Lys Bip Arg Val^(D)Pro^(L)Pro 13.2 66 2102.0 246. SEQ ID NO: 246 4ClPhe Trp Leu Lys LysArg Arg Bip Arg Bip Arg Val ^(D)Pro^(L)Pro 13.2 49 2102.0 247. SEQ IDNO: 247 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val ^(D)Pro-Gly 9.558 1838.3 248. SEQ ID NO: 248 Leu Arg Leu Lys Lys Arg Arg Trp Lys TyrArg Val ^(D)Pro-Arg 9.3 57 1937.4 249. SEQ ID NO: 249 Leu Arg Leu LysLys Arg Arg Trp Lys Tyr Arg Val ^(D)Pro-Tyr 9.9 29 1944.4 250. SEQ IDNO: 250 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val ^(D)Pro-Phe 10.734 1928.4 251. SEQ ID NO: 251 Leu Arg Leu Lys Lys Arg Arg Trp Lys TyrArg Val ^(D)Pro-Trp 10.7 25 1967.5 252. SEQ ID NO: 252 Leu Arg Leu LysLys Arg Arg Trp Lys Tyr Arg Val ^(D)Pro-Leu 10.5 21 1894.4 253. SEQ IDNO: 253 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val ^(D)Pro-Ile 10.442 1894.4 254. SEQ ID NO: 254 Leu Arg Leu Lys Lys Arg Arg Trp Lys TyrArg Val ^(D)Pro-Cha 11.2 36 1934.5 255. SEQ ID NO: 255 Leu Arg Leu LysLys Arg Arg Trp Lys Tyr Arg Val ^(D)Pro-2Nal 11.4 27 1978.5 Examples ex.256-286 (n = 12) All products were purified by preparativeHPLC-chromatography. Purities > 90%. Example Sequ. ID P1 P2 P3 P4 P5 P6P7 P8 P9 P10 P11 P12 Template MS 256. SEQ ID NO: 256 Leu Arg Leu Lys LysArg Arg Trp Lys Tyr Arg Val ^(D)Pro-A8′-1 1990.5 257. SEQ ID NO: 257 LeuArg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val ^(D)Pro-A8′-2 2018.3 258.SEQ ID NO: 258 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val^(D)Pro-A8′-3 2086.4 259. SEQ ID NO: 259 Leu Arg Leu Lys Lys Arg Arg TrpLys Tyr Arg Val ^(D)Pro-A8′-4 2086.4 260. SEQ ID NO: 260 Leu Arg Leu LysLys Arg Arg Trp Lys Tyr Arg Val ^(D)Pro-A8′-5 1978.3 261. SEQ ID NO: 261Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val ^(D)Pro-A8′-6 2023.3262. SEQ ID NO: 262 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val^(D)Pro-A8′-7 1934.3 263. SEQ ID NO: 263 Leu Arg Leu Lys Lys Arg Arg TrpLys Tyr Arg Val ^(D)Pro-A8′-8 1948.2 264. SEQ ID NO: 264 Leu Arg Leu LysLys Arg Arg Trp Lys Tyr Arg Val ^(D)Pro-A8′-9 1962.2 265. SEQ ID NO: 265Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val ^(D)Pro-A8′-10 1976.3266. SEQ ID NO: 266 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val^(D)Pro-A8′-11 1962.2 267. SEQ ID NO: 267 Leu Arg Leu Lys Lys Arg ArgTrp Lys Tyr Arg Val ^(D)Pro-A8′-12 2002.3 268. SEQ ID NO: 268 Leu ArgLeu Lys Lys Arg Arg Trp Lys Tyr Arg Val ^(D)Pro-A8′-13 2016.3 269. SEQID NO: 269 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val^(D)Pro-A8′-14 1976.3 270. SEQ ID NO: 270 Leu Arg Leu Lys Lys Arg ArgTrp Lys Tyr Arg Val ^(D)Pro-A8′-15 1996.2 271. SEQ ID NO: 271 Leu ArgLeu Lys Lys Arg Arg Trp Lys Tyr Arg Val ^(D)Pro-A8′-16 2011.4 272. SEQID NO: 272 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val^(D)Pro-A8′-17 2049.3 273. SEQ ID NO: 273 Leu Arg Leu Lys Lys Arg ArgTrp Lys Tyr Arg Val ^(D)Pro-A8′-18 2063.4 274. SEQ ID NO: 274 Leu ArgLeu Lys Lys Arg Arg Trp Lys Tyr Arg Val ^(D)Pro-A8′-19 2072.3 275. SEQID NO: 275 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val^(D)Pro-A8′-20 2046.4 276. SEQ ID NO: 276 Leu Arg Leu Lys Lys Gly ArgTrp Lys Tyr Arg Val ^(D)Pro^(L)Pro 1779.2 277. SEQ ID NO: 277 Leu ArgLeu Lys Lys Arg Arg Trp Lys Tyr Arg Val (c1)-1 2023.2 278. SEQ ID NO:278 Leu Tyr Leu Lys Lys Arg Arg Trp Lys Tyr Tyr Val ^(D)Pro^(L)Pro1892.3 279. SEQ ID NO: 279 Leu Trp Leu Lys Lys Arg Arg Trp Lys Tyr TyrVal ^(D)Pro^(L)Pro 1915.4 280. SEQ ID NO: 280 Arg Trp Leu Lys Lys ArgArg Trp Lys Tyr Trp Val ^(D)Pro^(L)Pro 1981.4 281. SEQ ID NO: 281 ArgTrp Leu Lys Lys Arg Arg Trp Lys Tyr Tyr Val ^(D)Pro^(L)Pro 1958.4 282.SEQ ID NO: 282 Leu Trp Leu Lys Lys Arg Arg Trp Lys Tyr Tyr Arg^(D)Pro^(L)Pro 1995.5 283. SEQ ID NO: 283 Leu Trp Leu Lys Lys Arg ArgTrp Lys Tyr Tyr Arg ^(D)Pro^(L)Pro 1972.4 284. SEQ ID NO: 284 Arg TrpLeu Lys Lys Arg Arg Trp Lys Tyr Tyr Arg ^(D)Pro^(L)Pro 2015.5 285. SEQID NO: 285 Leu Arg Leu Lys Lys Y(Bzl) Arg Trp Lys Tyr Arg Val^(D)Pro^(L)Pro 1975.5 286. SEQ ID NO: 286 Leu Arg Leu Lys Lys ^(D)Y(Bzl)Arg Trp Lys Tyr Arg Val ^(D)Pro^(L)Pro 1975.5 Examples ex. 287-300 (n =12) All products were purified by preparative HPLC-chromatography.Purities > 90%. 287. SEQ ID NO: 287 Bip Trp Leu Lys Lys Arg Arg Trp LysTyr Tyr Arg ^(D)Pro^(L)Pro 2082.6 288. SEQ ID NO: 288 Thr Trp Leu LysLys Arg Arg Trp Lys Tyr Tyr Arg ^(D)Pro^(L)Pro 1960.4 289. SEQ ID NO:289 Arg Bip Leu Lys Lys Arg Arg Trp Lys Tyr Tyr Arg ^(D)Pro^(L)Pro2052.5 290. SEQ ID NO: 290 Arg Thr Leu Lys Lys Arg Arg Trp Lys Tyr TyrArg ^(D)Pro^(L)Pro 1930.4 291. SEQ ID NO: 291 Arg Trp Thr Lys Lys ArgArg Trp Lys Tyr Tyr Arg ^(D)Pro^(L)Pro 2003.4 292. SEQ ID NO: 292 ArgTrp Leu Arg Lys Arg Arg Trp Lys Tyr Tyr Arg ^(D)Pro^(L)Pro 2043.5 293.SEQ ID NO: 293 Arg Trp Leu Gln Lys Arg Arg Trp Lys Tyr Tyr Arg^(D)Pro^(L)Pro 2015.4 294. SEQ ID NO: 294 Lys Trp Leu Lys Lys Arg ArgTrp Lys Tyr Tyr Arg ^(D)Pro^(L)Pro 1987.5 295. SEQ ID NO: 295 Tyr TrpLeu Lys Lys Arg Arg Trp Lys Tyr Tyr Arg ^(D)Pro^(L)Pro 2022.5 296. SEQID NO: 296 Trp Trp Leu Lys Lys Arg Arg Trp Lys Tyr Tyr Arg^(D)Pro^(L)Pro 2045.5 297. SEQ ID NO: 297 Val Trp Leu Lys Lys Arg ArgTrp Lys Tyr Tyr Arg ^(D)Pro^(L)Pro 2082.4 298. SEQ ID NO: 298 Gln TrpLeu Lys Lys Arg Arg Trp Lys Tyr Tyr Arg ^(D)Pro^(L)Pro 1987.4 299. SEQID NO: 299 Cha Trp Leu Lys Lys Arg Arg Trp Lys Tyr Tyr Arg^(D)Pro^(L)Pro 2012.5 300. SEQ ID NO: 300 Y Trp Leu Lys Lys Arg Arg TrpLys Tyr Tyr Arg ^(D)Pro^(L)Pro 2112.6 (bzl)

[1090] 1.2. Procedure 2

[1091] Examples ex.256-275 were also synthesized using procedure 2.

[1092] The peptide synthesis was carried out by solid phase method usingstandard Fmoc chemistry on a peptide synthesizer-ABI 433A.

[1093] The first amino acid, Fmoc-Arg(Pbf)-OH (1.29g, 1.2 equiv.) wascoupled to the 2-chlorotritylchloride resin (Barlos et al. TetrahedronLett. 1989, 30, 3943-3946) (2g, 0.83 mmol/g) in presence of DIEA (1.12mL, 4 equiv.) in CH₂Cl₂ (20 mL), with swirling for 3 hr at roomtemperature. The resin was then washed with 3×CH₂Cl₂/MeOH/DIEA(17:2:1),3×CH₂Cl₂, 2×DMF, 2×CH₂Cl₂, 2×MeOH. Finally, the resin was dried undervacuum and the substitution level was measured by weight increase (˜0.6mmol/g)

[1094] The resin with the synthesized linear peptide,Fmoc-Arg(Pbf)-Trp(Boc)-Lys(Boc)-Tyr(tBu)-Arg(Pbf)-Val-^(D)Pro-212-Leu-Arg(Pbf)-Leu-Lys(Boc)Lys(Boc)-Arg(Pbf)-resin,was preferably divided into equal parts and placed in different reactionvessels in order to carry out the acylation reaction in parallel format.The coupling and deprotection reactions in the following steps weremonitored by Kaiser's test (Kaiser et al. Anal. Biochemistry 1970, 43,595).

[1095] Removal of Alloc Protecting Group:

[1096] To the linear peptide resin (100 mg in each reaction vessel) wasadded Pd(PPh₃)₄ (15 mg, 0.5 equiv.) under argon followed by dry CH₂Cl₂(10 mL) and phenylsilane (17 μL, 30 equiv.). The reaction mixture wasleft for 1 hour in the dark, filtered, and the resin was washed twicewith CH₂Cl₂, DMF, and CH₂Cl₂.

[1097] Acylation of 4-amino-proline Group

[1098] To the resin was added the corresponding acylating agent (usuallya carboxyxlic acid (R^(64′)COOH, 3 equiv.), HBTU (22.3 mg, 4 equiv.),HOBt (8 mg, 4 equiv.) and DIEA (125 μL, 6 equiv.) in DMF (2 mL) for1.5-2 hrs at room temperature. The resin was filtered, washed with2×DMF, 3×CH₂Cl₂, 2×DMF.

[1099] Deprotection of N^(α)-Fmoc Group:

[1100] Deprotection of the Fmoc-group was achieved by treating the resinwith 20% piperidine in DMF for 20 min. The resin was subsequentlyfiltered and washed three times with DMF, and CH₁Cl₂, and twice withDMF, and CH₂Cl₂.

[1101] Cleavage of Peptide from the Resin:

[1102] The linear side-chain protected peptide was cleaved from theresin using AcOH: TFE: CH₂Cl₂ (2:2:6, v/v/v) for 2 hrs at roomtemperature. The resin was filtered off and washed twice with a mixtureof AcOH:TFE:DCM and once with CH₂Cl₂. The filtrate was subsequentlydiluted with hexane (14 times by vol.) and concentrated. Evaporation wasrepeated twice with hexane to remove traces of AcOH. The residue wasdried under vacuum. Yield of the linear protected peptide was generallyabout 40-50 mg.

[1103] Cyclization of the Linear Protected Peptide:

[1104] Cyclization was carried out in DMF at a concentration of 5 mg/mLusing HATU (13.12 mg, 3 equiv.), HOAT (4.7 mg, 3 equiv.), DIEA (153 μL,6 equiv.). The reaction mixture was stirred for 16 hrs at roomtemperature and the completion of reaction was monitored by HPLC. Afterthe evaporation of DMF, CH₃CN/H₂O (90/10, v/v) was added to the residueand extracted with DCM. The organic layer was washed once with water andevaporated to dryness. Dried under vacuum.

[1105] Cleavage of Side Chain Protecting Groups:

[1106] The final deprotection of the side-chain protecting groups wascarried out by treating the peptide with TFA:triisopropylsilane:H₂O(95:2.5:2.5, v/v/v) at room temperature for 3 hrs. TFA was thenevaporated and the residue triturated with cold ether.

[1107] Purification:

[1108] The crude peptides thus obtained were analyzed and purified byHPLC on a VYDAC C18 preparative column using 5-60% CH₃CN/H₂O+0.1% TFA in30 min as gradient and a flow rate of 10 ml/min. The purity of the finalpeptide was checked by analytical HPLC and by ESI-MS. Analytical dataare shown in table 7.

[1109] 1.3. Procedure 3

[1110] Procedure 3 describes the synthesis of peptides having disulfideβ-strand linkages.

[1111] a) n=8::The peptides are synthesized according to procedure 1starting with the amino acid at position P4, coupled to the resin. Thelinear peptides are synthesized on solid support according to procedure1 in the following sequence: P5-P6-P7-P8-^(D)Pro-P1-P2-P3-P4-resin,where at positions P2 and n Fmoc-Cys(Acm)OH or Fmoc-hCys(Acm)OH areincorporated. The linear peptides are cleaved and cyclized as describedin procedure 1. The cyclized side chain protected β-hairpin mimetics aredissolved in methanol (0.5 ml) to which is added dropwise a solution ofiodine in methanol (1N, 1.5 equiv.) at room temperature. The reactionmixture is stirred for 4 hours at room temperature and the solventevaporated. The crude product is subsequently deprotected and purifiedas described in procedure 1.

[1112] b) n=9::The peptides are synthesized according to procedure 1starting with the amino acid at position P5, coupled to the resin. Thelinear peptides are synthesized on solid support according to procedure1 in the following sequence:P6-P7-P8-P9-^(D)Pro-Pro-P1-P2-P3-P4-P5-resin, where at positions P2 andP8 Fmoc-Cys(Acm)OH or Fmoc-hCys(Acm)OH are incorporated. The linearpeptides are cleaved and cyclized as described in procedure 1. Thecyclized side chain protected β-hairpin mimetics are dissolved inmethanol (0.5 ml) to which is added dropwise a solution of iodine inmethanol (1N, 1.5 equiv.) at room temperature. The reaction mixture isstirred for 4 hours at room temperature and the solvent evaporated. Thecrude product is subsequently deprotected and purified as described inprocedure 1.

[1113] c) n=10::The peptides are synthesized according to procedure 1starting with the amino acid at position P5, coupled to the resin. Thelinear peptides are synthesized on solid support according to procedure1 in the following sequence:P6-P7-P8-P9-P10-^(D)Pro-P1-P2-P3-P4-P5-resin, where at positions P3 andP8 Fmoc-Cys(Acm)OH or Fmoc-hCys(Acm)OH are incorporated. The linearpeptides are cleaved and cyclized as described in procedure 1. Thecyclized side chain protected β-hairpin mimetics are dissolved inmethanol (0.5 ml) to which is added dropwise a solution of iodine inmethanol (1N, 1.5 equiv.) at room temperature. The reaction mixture isstirred for 4 hours at room temperature and the solvent evaporated. Thecrude product is subsequently deprotected and purified as described inprocedure 1.

[1114] d) n=11::The peptides are synthesized according to procedure 1starting with the amino acid at position P5, coupled to the resin. Thelinear peptides are synthesized on solid support according to procedure1 in the following sequence:P6-P7-P8P9-P10-P11-^(D)Pro-P1-P2-P3-P4-P5-resin, orP6-P7-P8-P9-P10-P11-^(D)Pro-Pro-P1-P2-P3-P4, orP5-P6-P7-P8-P9-P10-P11-^(D)Pro-Pro-P1-P2-P3-P4P5-resin, where atpositions P2, P4, P8 and P10 Fmoc-Cys(Acm)OH or Fmoc-hCys(Acm)OH areincorporated. The linear peptides are cleaved and cyclized as describedin procedure 1. The cyclized side chain protected β-hairpin mimetics aredissolved in methanol (0.5 ml) to which is added dropwise a solution ofiodine in methanol (1N, 1.5 equiv.) at room temperature. The reactionmixture is stirred for 4 hours at room temperature and the solventevaporated. The crude product is subsequently deprotected and purifiedas described in procedure 1.

[1115] e) n=12::The peptides are synthesized according to procedure 1starting with the amino acid at position P6, coupled to the resin. Thelinear peptides are synthesized on solid support according to procedure1 in the following sequence;P7-P8-P9-P10-P11-P12-^(D)Pro-Pro-P1-P2-P3-P4-P5-P6-resin, orP7-P8-P9-P10-P11-^(D)Pro-Pro-P1-P2-P3-P4-P5-P6-resin, orP7-P8-P9-P10-P11-^(D)Pro-Pro-P1-P2-P3-P4-P5-P6-resin, where at positionsP2, P4, P9 and P11 Fmoc-Cys(Acm)OH or Fmoc-hCys(Acm)OH are incorporated.The linear peptides are cleaved and cyclized as described inprocedure 1. The cyclized side chain protected β-hairpin mimetics aredissolved in methanol (0.5 ml) to which is added dropwise a solution ofiodine in methanol (1N, 1.5 equiv.) at room temperature. The reactionmixture is stirred for 4 hours at room temperature and the solventevaporated. The crude product is subsequently deprotected and purifiedas described in procedure 1.

[1116] Following procedure 3NH₂Arg(Pbf)-Lys(Boc)-Lys(Boc)-Cys(Acm)-Arg(Pbf)-Leu-Pro-^(D)Pro-Val-Arg-Cys(Acm)-Lys(Boc)-Trp(Boc)-Arg(Pbf)-[SEQID NO:301], coupled to the resin, was synthesized on the resin, thelinear side-chain protected peptide cleaved and cyclized, followed bydisulfide formation, deprotection and preparative HPLC chromatographyyielding the above product [SEQ ID NO:302] as a white amorphous powder.ESI-MS: 1806.2 ([M+H]+).

[1117] f) n=14::The peptides are synthesized according to procedure 1starting with the amino acid at position P7, coupled to the resin. Thelinear peptides are synthesized on solid support according to procedure1 in the following sequence:P8-P9-P10-P11-P12-P13-P14-^(D)Pro-Pro-P1-P2-P3-P4-P5-P6-P7-resin, orP8-P9-P10-P11-P12-P13-P14-^(D)Pro-Pro-P1-P2-P3-P4-P5-P6-P7-resin, orP8-P9-P10-P11-P12-P14-^(D)Pro-P1-P2-P3-P4-P5-P6-P7-resin, where atpositions P3, P5, P10 and P12 Fmoc-Cys(Acm)OH or Fmoc-hCys(Acm)OH areincorporated. The linear peptides are cleaved and cyclized as describedin procedure 1. The cyclized side chain protected β-hairpin mimetics aredissolved in methanol (0.5 ml) to which is added dropwise a solution ofiodine in methanol (1N, 1.5 equiv.) at room temperature. The reactionmixture is stirred for 4 hours at room temperature and the solventevaporated. The crude product is subsequently deprotected and purifiedas described in procedure 1.

[1118] g) n=16::The peptides are synthesized according to procedure 1starting with the amino acid at position P8, coupled to the resin. Thelinear peptides are synthesized on solid support according to procedure1 in the following sequence:P9-P10-P11-P12-P13-P14-P15-P16-^(D)Pro-Pro-P1-P2-P3-P4-P5-P6-P7-P8-resin,orP9-P10-P11-P12-P13-P14-P15-P16-^(D)Pro-Pro-P1-P2-P3-P4-P5-P6-P7-P8-resin,orP9-P10-P11-P12-P13-P14-P15-P16-^(D)Pro-Pro-P1-P2-P3-P4-P5-P6-P7-P8-resin,orP9-P10-P11-P12-P13-P14-P15-P16-^(D)Pro-Pro-P1-P2-P3-P4P5-P6-P7-P8-resin,orP9-P10-P11-P12-P13-P14-P51-P16-^(D)Pro-Pro-P1-P2-P3-P4-P5-P6-P7-P8-resin,orP9-P10-P11-P12-P13-P14-P15-P16-^(D)Pro-Pro-P1-P2-P3-P4-P5-P6-P7-P8-resin,orP9-P10-P11-P12-P13-P14-P15-P16-^(D)Pro-Pro-P1-P2-P3-P4-P5-P6-P7-P8-resin,where at positions P2, P4, P6, P11, P13 and P15 Fmoc-Cys(Acm)OH orFmoc-hCys(Acm)OH are incorporated. The linear peptides are cleaved andcyclized as described in procedure 1. The cyclized side chain protectedβ-hairpin mimetics are dissolved in methanol (0.5 ml) to which is addeddropwise a solution of iodine in methanol (1N, 1.5 equiv.) at roomtemperature. The reaction mixture is stirred for 4 hours at roomtemperature and the solvent evaporated. The crude product issubsequently deprotected and purified as described in procedure 1.

[1119] 1.4. Procedure 4

[1120] Procedure 4 describes the synthesis of peptides having amideβ-strand linkages.

[1121] a) n=8::The peptides are synthesized according to procedure 1starting with the amino acid at position P4, coupled to the resin. Thelinear peptides are synthesized on solid support according to procedure1 in the following sequence: P5-P6-P7-P8-^(D)Pro-Pro-P1-P2-P3-P4-resin,where at position P2 Fmoc-Asp(OAllyl)OH or Fmoc-Glu(OAllyl)OH, and atposition P7 Fmoc-Orn(Alloc)OH or Fmoc-Lys(Alloc)OH are incorporated.Alternatively, at position P2 Fmoc-Orn(Alloc)OH or Fmoc-Lys(Alloc)OH,and at position P7 Fmoc-Asp(OAllyl)OH or Fmoc-Glu(OAllyl)OH areincorporated. The linear peptides are cleaved and cyclized, and theallyl groups are removed as described in procedure 2. The amide linkageis subsequently performed as described for the cyclization according toprocedures 1 and 2, the side chain protective groups are removed and theproducts are purified as described in procedures 1 and 2.

[1122] b) n—9::The peptides are synthesized according to procedure 1starting with the amino acid at position P5, coupled to the resin. Thelinear peptides are synthesized on solid support according to procedure1 in the following sequence:P6-P7-P8-P9-^(D)Pro-Pro-P1-P2-P3-P4-P5-resin, where at position P2Fmoc-Asp(OAllyl)OH or Fmoc-Glu(OAllyl)OH, and at position P8Fmoc-Orn(Alloc)OH or Fmoc-Lys(Alloc)OH are incorporated. Alternatively,at position P2 Fmoc-Orn(Alloc)OH or Fmoc-Lys(Alloc)OH, and at positionP8 Fmoc-Asp(OAllyl)OH or Fmoc-Glu(OAllyl)OH are incorporated. The linearpeptides are cleaved and cyclized, and the allyl groups are removed asdescribed in procedure 2. The amide linkage is subsequently performed asdescribed for the cyclization according to procedures 1 and 2, the sidechain protective groups are removed and the products are purified asdescribed in procedures 1 and 2.

[1123] c) n=10::The peptides are synthesized according to procedure 1starting with the amino acid at position P5, coupled to the resin. Thelinear peptides are synthesized on solid support according to procedure1 in the following sequence:P6-P7-P5-P9-P10-^(D)Pro-Pro-P1-P2-P3-P4-P5-resin, where at position nFmoc-Asp(OAllyl)OH or Fmoc-Glu(OAllyl)OH, and at position P8Fmoc-Orn(Alloc)OH or Fmoc-Lys(Alloc)OH are incorporated. Alternatively,at position P3 Fmoc-Orn(Alloc)OH or Fmoc-Lys(Alloc)OH, and at positionP8 Fmoc-Asp(OAllyl)OH or Fmoc-Glu(OAllyl)OH are incorporated. The linearpeptides are cleaved and cyclized, and the allyl groups are removed asdescribed in procedure 2. The amide linkage is subsequently performed asdescribed for the cyclization according to procedures 1 and 2, the sidechain protective groups are removed and the products are purified asdescribed in procedures 1 and 2.

[1124] d) n=11:: The peptides are synthesized according to procedure 1starting with the amino acid at position P5, coupled to the resin. Thelinear peptides are synthesized on solid support according to procedure1 in the following sequence:P6-P7-P8-P9-P10-P11-^(D)Pro-Pro-P1-P2-P3-P4-P5-resin, orP6-P7-P8-P9-P10-P11-Pro-Pro-P1-P2-P3-P4-P5-resin, orP6-P7-P8-P9-P10-P11-^(D)Pro-Pro-P1-P2-P3-P4-P5-resin; where at positionsP2 and/or P4 Fmoc-Asp(OAllyl)OH or Fmoc-Glu(OAllyl)OH, and at positionsP8 and/or P10 Fmoc-Orn(Alloc)OH or Fmoc-Lys(Alloc)OH are incorporated.Alternatively, at positions P2 and/or P4 Fmoc-Orn(Alloc)OH orFmoc-Lys(Alloc)OH, and at positions P8 and/or P10 Fmoc-Asp(OAllyl)OH orFmoc-Glu(OAllyl)OH are incorporated. The linear peptides are cleaved andcyclized, and the allyl groups are removed as described in procedure 2.The amide linkage is subsequently performed as described for thecyclization according to procedures 1 and 2, the side chain protectivegroups are removed and the products are purified as described inprocedures 1 and 2.

[1125] e) n=12::The peptides are synthesized according to procedure 1starting with the amino acid at position P6, coupled to the resin. Thelinear peptides are synthesized on solid support according to procedure1 in the following sequence:P7-P8-P9-P10-P11-P12-^(D)Pro-Pro-P1-P2-P3-P4-P5-P6-resin, orP7-P8-P9-P10-P11-P12-^(D)Pro-Pro-P1-P2-P3-P4-P5-P6-resin, orP7-P8-P9-P10-P11-P12-^(D)Pro-Pro-P1-P2-P3-P4-P5-P6-resin; where atpositions P2 and/or P4 Fmoc-Asp(OAllyl)OH or Fmoc-Glu(OAllyl)OH, and atpositions P9 and/or P11 Fmoc-Orn(Alloc)OH or Fmoc-Lys(Alloc)OH areincorporated. Alternatively, at positions P2 and/or P4 Fmoc-Orn(Alloc)OHor Fmoc-Lys(Alloc)OH, and at positions P9 and/or P11 Fmoc-Asp(OAllyl)OHor Fmoc-Glu(OAllyl)OH are incorporated. The linear peptides are cleavedand cyclized, and the allyl groups are removed as described in procedure2. The amide linkage is subsequently performed as described for thecyclization according to procedures 1 and 2, the side chain protectivegroups are removed and the products are purified as described inprocedures 1 and 2.

[1126] f) n=14: The peptides are synthesized according to procedure 1starting with the amino acid at position P7, coupled to the resin. Thelinear peptides are synthesized on solid support according to procedure1 in the following sequence:P8-P9-P10-P11-P12-P3-P14-^(D)Pro-Pro-P1-P2-P3-P4-P5-P6-P7-resin, orP8-P9-P10-P11-P12-P13-P14-Pro-Pro-P1-P2-P3-P4-P5-P6-P7-resin, orP8-P9-P10-P11-P12-R14-^(D)Pro-Pro-P1-P2-P3-P4-P5P6-P7-resin; where atpositions P3 and/or P5 Fmoc-Asp(OAllyl)OH or Fmoc-Glu(OAllyl)OH, and atpositions P10 and/or P12 Fmoc-Orn(Alloc)OH or Fmoc-Lys(Alloc)OH areincorporated. Alternatively, at positions P3 and/or P5 Fmoc-Orn(Alloc)OHor Fmoc-Lys(Alloc)OH, and at positions P10 and/or P12 Fmoc-Asp(OAllyl)OHor Fmoc-Glu(OAllyl)OH are incorporated. The linear peptides are cleavedand cyclized, and the allyl groups are removed as described in procedure2. The amide linkage was subsequently performed as described for thecyclization according to procedures 1 and 2, the side chain protectivegroups are removed and the products are purified as described inprocedures 1 and 2.

[1127] g) n=16::The peptides are synthesized according to procedure 1starting with the amino acid at position P7, coupled to the resin. Thelinear peptides are synthesized on solid support according to procedure1 in the following sequence:P8-P9-P10-P11-P12-P13-P14-P15-P16-^(D)Pro-Pro-P1-P2-P3-P4-P5-P6-P7-resin,orP8-P9-P10-P11-P12-P13-P14P15-P16-^(D)Pro-Pro-P1-P2-P3-P4-P5-P6-P7-resin,or P9-P9-P10-P11-P12-P4-P5-P16-^(D)Pro-Pro-P1-P2-P3-P4-P5-P6-P7-resin,or P8-P9-P10-P11-P12-P13-P14P15-P16-“Pro-Pro-P1-P2-P3-P4-P5-P6-P7-resin,orP8-P9-P10-P11-P12-P13-P14-P15-P16-^(D)Pro-Pro-P1-P2-P3-P4-P5-P6-P7-resin,orP8-P9-P10-P11-P12-P13-P14-P15-P16-^(D)Pro-Pro-P1-P2-P3-P4-P5-P6-P7-resin,orP8-P9-P10-P11-P12-P13-P14-P15-P16-^(D)Pro-Pro-P1-P2-P3-P4-P5-P6-P7-resin;where at positions P2 and/or P4 and/or P6 Fmoc-Asp(OAllyl)OH orFmoc-Glu(OAllyl)OH, and at positions P11 and/or P13 and/or P15Fmoc-Orn(Alloc)OH or Fmoc-Lys(Alloc)OH are incorporated. Alternatively,at positions P2 and/or P4 and/or P6 Fmoc-Orn(Alloc)OH orFmoc-Lys(Alloc)OH, and at positions P11 and/or P13 and/or P15Fmoc-Asp(OAllyl)OH or Fmoc-Glu(OAllyl)OH are incorporated. The linearpeptides are cleaved and cyclized, and the allyl groups are removed asdescribed in procedure 2. The amide linkage is subsequently performed asdescribed for the cyclization according to procedures 1 and 2, the sidechain protective groups are removed and the products are purified asdescribed in procedures 1 and 2.

[1128] Following procedure 2NH₂Arg(Pbf)-Trp(Boc)-Lys(Boc)-Tyr(tBu)-Arg(Pbf-^(D)Pro-212-Leu-Arg(Pbf)-Leu-Lys(Boc)-Lys(Boc)-Arg(Pbf)-[SEQID NO:303], coupled to the resin, was prepared, the linear peptidecleaved and cyclized. The Alloc-group was removed from building block212 as described in procedure 2, half of the resulting amine reactedwith excess glutaric anhydride in pyridine and DMAP and the solventswere removed. The resulting acid was coupled with the second half of theabove mentioned amine in DMF and in the presence of TATU, HOAt and DIEA.The protective groups were removed as described in procedure 2 and theproduct purified by preparative HPLC chromatography as described inprocedure 2 to yield the above product [SEQ ID NO:304] as a whiteamorphous powder. ESI-MS: 3882.3 ([M+H]⁺).

[1129] 2. Synthesis of Templates

[1130] 2.1. The synthesis of(2S,4S)[(Allyloxy)carbonylamino]-1-[(9H-fluoren-9-yl)methoxycarbonyl]-proline(212) and(2S,4R)-4-[(Allyloxy)carbonylamino]-1-[(9H-fluoren-9-yl)methoxy-carbonyl]proline(217) are shown in Schemes 42 and 43.

[1131](2S,46)-4-[(Allyloxy)carbonylamino]-1-[(9H-fluoren-9-yl)methoxycarbonyl]-proline(212)

[1132] i,ii: To a solution of (2S,4R)-4-hydroxyproline (30 g, 0.18 mol)in abs. methanol (300 ml) at 0° C. thionyl chloride (38 ml, 2.5 eq, 0.45mol) was added dropwise. The solution was heated to reflux and stirredfor 3 h under nitrogen. Then the solution was concentrated by rotaryevaporation and the ester precipitated by adding diethylether. Afterfiltration the white solid was washed with diethylether, then dried atHV: (2S,4R)₄-hydroxyproline-methylester-hydrochloride as a white solid(29.9 g, 90%). %). TLC (CH₂Cl₂/MeOH/water 70:28:2): R_(f) 0.82. [α]_(D)²⁰=−24.5 (c=1.01, MeOH). IR (KBr): 3378s (br.), 2950m, 2863w, 1745s,1700s, 1590 m, 1450s, 1415s, 1360s, 1215s, 1185s, 1080m, 700m. ¹H-NMR(300 MHz, MeOH-d₄) 4.66-4.55 (m, 2H, H—C(4), H—C(2)); 3.85 (s, 3H,H₃-CO); 3.45 (dd, J=12.2, 3.8, 1H, H—C(5)); 3.37-3.25 (m, 1H, H—C(5));2.44-2.34 (m, 1H, H—C(3)), 2.27-2.12 (m, 1H, H—C(3)). ¹³C-NMR (75 MHz,MeOH-d₄): 170.8 (s, COOMe); 70.8 (d, C(4)); 59.6 (d, C(2)); 55.2 (t,C(5)); 54.2 (q, Me); 38.7 (t, C(3)). CI-MS (NH₃): 146.1 ([M-Cl]⁺). 30 g(0.17 mmol) of the above intermediate was dissolved in CH₂Cl₂ (300 nml),cooled to 0° C. and triethylamine (45 ml, 1.5 eq, 0.25 mol) was addeddropwise. Then di-tert.-butyldicarbonate (54.0 g, 1.5 eq, 0.25 mmol) inCH₁Cl₂ (15 ml) and 4-N,N-dimethylaminopyridine (2.50 g, 0.1 eq, 17 mmol)was added and the solution stirred at room temperature overnight. Thenthe solution was washed with 1N aq. citric acid solution, sat. aq.NaHCO₃ solution, dried (Na₂SO₄), evaporated and the residue dried athigh vaccum:(2S,4R)-4-Hydroxy-1-[(tert-butoxy)carbonyl]proline-methylester (209) asa white solid (39.6 g, 78%). TLC (CH₂Cl₂/MeOH 9:1): R_(f) 0.55. [α]_(D)²⁴=−55.9 (c=0.983, CHCl₃). IR (KBr): 3615w, 3440w (br.), 2980m, 2950m,2880m, 1750s, 1705s, 1680s, 1480 m, 1410s, 1370s, 1340m, 1200s, 1160s,1130m, 1090m, 1055w, 960w, 915w, 895w, 855m, 715m. ¹H-NMR (300 MHz,CDCl₃): 4.47-4.37 (m, 2H, H—C(4), H—C(2)); 3.73 (s, 3H, H₃C—O)); 3.62(dd, J=11.8, 4.1, 1H, H—C(5)); 3.54-3.44 (m, 1H, H—C(5)); 2.32-2.25 (m,1H, H—C(3)); 2.10-2.03 (m, 1H, H—C(3)); 1.46+1.41 (2s, 9H, tBu). ¹³C-NMR(75 MHz, CDCl₃): 173.6 (s, COOMe); 154.3+153.9 (2s, COOtBu); 80.3 (s,C-tBu); 70.0+69.3 (2d, C(4)); 57.9+57.4 (2d, C(2)); 54.6 (t, C(5)); 51.9(q, Me); 39.0+38.4 (2t, C(3)); 28.1+27.6 (2q, tBu). CI-MS: 246.2([M+H]⁺); 190.1 ([M-tBu+H]⁺); 146.1 ((M-BOC+H]⁺).

[1133] iii,iv: 39 g (0.16 mol) of 209 was dissolved in CH₂Cl₂ (300 ml)followed by addition of 4-nitrobenzenesulfonyl chloride (46 g, 1.3 eq,0.21 mol) and Et₃N (33 ml, 1.5 eq, 0.24 mol) at 0° C. Then the solutionwas stirred overnight and brought gradually to room temperature, washedwith 1N hydrochloric acid, sat. aq. NaHCO₃ solution and dried (Na₂SO₄).The solvents were evaporated and the crude product was purified byfiltration on silica gel with (2:1) hexane/AcOEt. The product wascrystallized from hexane/AcOEt (2S,4S)4[(p-nitrobenzyl)sulfonyloxy]-1-[(tert-butoxy)carbonyl]prolinemethylester as white crystals (46.4 g, 65%). TLC (hexane/AcOEt 1:1):R_(f) 0.78. M.p.: 93-95° C. [α]_(D) ²⁰=−32.3° (c=0.907, CHCl₃). IR(KBr): 3110w, 3071w, 2971w, 1745s, 1696s, 1609s, 1532s, 1414s, 1365s,1348m, 1289m, 1190m, 1173m, 1122w, 1097w, 1043w, 954w, 912w, 755w, 578w.¹H-NMR (600 MHz, CDCl₃): 8.42-8.34 (m, 2H, H-C(Nos)); 8.11-8.04 (m, 2H,H—C(Nos)); 5.14 (s, 1H, H—C(4)); 4.39-4.28 (m, 1H, H—C(2)); 3.70-3.56(m, 5H, H₂—C(5), H₃C—O); 2.58-2.38 (m, 1H, H—C(3)); 2.25-2.11 (m, 1H,H—C(3)); 1.37+1.33 (2s, 9H, tBu). ¹³C-NMR (150 MHz, CDCl₃): 172.4+172.2(2s, COOMe); 153.6+153.0 (2s, COOtBu); 150.8+142.0 (2s, C(Nos));129.0+124.6 (2d, C(Nos)); 80.4 (s, C-tBu); 80.8+79.9 (2d, C(4));57.1+56.9 (2d, C(2)); 52.2+51.7 (2t, C(5)); 52.3 (q, Me); 37.1+35.9 (2t,C(3)); 28.0 (q, tBu). ESI-MS (MeOH+NaI): 453.0 ([M+NaI+).

[1134] 38 g (88 mmol) of the above intermediate was dissolved in DMF(450 ml) then heated to 40° C. when sodium azide (34 g, 6 eq, 0.53 mol)was added and the solution stirred overnight. DMF was evaporated and thesolid suspended in diethylether. The suspension was washed with waterand dried (Na₂SO₄). The solvent was evaporated and the product dried athigh vacuum: (2S,4S)-4-Azido-1-[(tert-butoxy)carbonyl]prolinemethylester (210) yellow oil (21.1 g, 88%). [α]_(D) ²⁰=−36.9 (c=0.965,CHCl₃). ¹H-NMR (600 MHz, CDCl₃): 4.46-4.25 (2m, 1H, H—C(2)); 4.20-4.10(m, 1H, H—C(4)); 3.80-3.65 (m, 4H, H—C(5), H₃C—O); 3.53-3.41 (m, 1H,H—C(5)); 2.54-2.39 (m, 1H, H—C(3)); 2.21-2.12 (m, 1H, H—C(3)); 1.47+1.41(2s, 9H, tBu). ¹³C-NMR (150 MHz, CDCl₃): 172.2+171.9 (2s, COOMe);153.9+153.4 (2s, COOtBu); 80.5 (s, C-tBu); 59.2+58.2 (2d, C(4));57.7+57.3 (2d, C(2)); 52.4+52.2 (2q, Me); 51.2+50.7 (2t, C(5));36.0+35.0 (2t, C(3)); 28.3+28.2 (2q, tBu). EI-MS (70ev): 270.1 ([M]⁺);227.1 ([M-CO₂+H]⁺); 169.1 ([M-BOC+H]⁺);.

[1135] v, vi: 21.1 g (78 mmol) of the above intermediate was dissolvedin a (3:1)-mixture of dioxane/water (500 ml) and SnCl₂ (59.2 g, 4 eq,0.31 mol) was added at O and the solution stirred for 30 min. andgraduallly brought to room temperature and stirred for another 5h Afteradjusting the pH to 8 with solid NaHCO₃, allyl chloroformate (41.5 ml, 5eq, 0.39 mol) was added and the solution stirred at room temperatureovernight. The reaction mixture was evaporated and extracted with AcOEt.The organic phase was washed with brine, dried (Na₂SO₄), the solventevaporated and the product was dried at high vacuum:(2S,4S)-4-((Allyloxy)carbonylamino]-1-[(tert-butoxy)carbonyl]prolinemethylester (211) as a clear thick oil (22.3 g, 87%). [α]_(D) ²⁰=−30.2°(c=1.25, CHCl₃). ¹H-NMR (300 MHz, CDCl₃): 5.98-5.77 (m, 1H,H—C(β)(Alloc)); 5.32-5.12 (m, 2H, H₂—C(γ)(Alloc); 4.59-4.46 (m, 2H,H₂—C(α)(Alloc)); 4.40-4.16 (m, 2H, H—C(4), H—C(2)); 3.80-3.53 (m, 4H,H—C(5), H₃C—O); 3.53-3.31 (m, 1H, H—C(5)); 2.54-2.17 (m, 1H, H—C(3));1.98-1.84 (m, 1H, H—C(3)); 1.41+1.37 (2s, 9H, tBu). ESI-MS(MeOH+CH₂Cl₂): 351.2 ([M+Na]⁺); 229.0 ([M-BOC+H]⁺).

[1136] vii-ix: 22 g, 67 mmol) of 211 was dissolved in a (4:1)-mixture ofmethanol/water (100 ml) and LiOH (5 g, 2 eq, 134 mmol) was added at roomtemperature and the solution stirred for 3.5 h. The reaction mixture wasevaporated and extracted with 1N hydrochloric acid (100 ml) and AcOEt.The solvent was removed and the resulting solid dissolved in 1:1TFA/CH₂Cl₂ (200 ml) and stirred for 2 h. The solvents were evaporatedand the product dried at high vacuum:(2S,4S)-4-[(Allyloxy)carbonylamino]proline as a clear oil (21 g, 96%)¹H-NMR (600 MHz, MeOH-d₄): 5.98-5.85 (m, 1H, H—C(β)(Alloc)); 5.30 (dd,J=17.1, 1.5 Hz, 1H, H—C(γ)(Alloc)); 5.12 (d, J=10.7 Hz, 1H,H—C(γ)(Alloc)); 4.54 (d, J=4.4 Hz, 2H, H₂—C(α)(Alloc)); 4.44 (t, J=8.9Hz, 1H, H—C(2)); 4.36-4.27 (m, 1H, H—C(4)); 3.58 (dd, 3=12.2, 7.3 Hz,1H, H—C(5)); 3.34-3.32 (m, 1H, H—C(5)); 2.73 (ddd, J=13.6, 8.7, 7.2 Hz,1H, H—C(3)); 2.23-2.15 (m, 1H, H—C(3)). ¹³CNMR (150 MHz, MeOH-d₄): 171.3(s, COOMe); 158.3 (s, COOAllyl); 134.1 (d, C(β)(Alloc)); 118.0 (t,C(γ)(Alloc)); 66.8 (t, C(α)(Alloc)); 59.7 (d, C(2)); 51.3 (d, C(4));51.1 (t, C(5)); 34.9 (t, C(3)). ESI-MS (DCM+MeOH): 237.0 ([M+Na]⁺);215.0 ([M+H]⁺).

[1137] 15 g (70 mmol) of the above intermediate and9-fluorenylmethoxycarbonylsuccinimid (28 g, 1.2 eq, 84 mmol) weredissolved in DCM (700 ml) and DIEA (48 ml, 6 eq, 0.42 mol) was added andthe solution stirred overnight at room temperature. The solvent wasremoved and the residue dissolved in AcOEt and washed with 1Nhydrochloric acid and dried (Na₂SO₄). After evaporation, the crudeproduct was purified by filtration on silica gel with a gradient of(3:1) hexane/AcOEt to AcOEt. The solvent was evaporated and the residuecrystallized from hexane at −20° C. The product was dried at highvacuum:(2S,4S)₄-[(Allyloxy)carbonylamino]-1-[(9H-fluoren-9-yl)methoxycarbonyl]-proline(212) as a white solid (23.8 mg, 78%) [α]_(D) ²⁰=−27.0 (c=1.1, CHCl₃).IR (KBr): 3321w (br.), 3066w, 2953w, 1707s, 1530m, 1451s, 1422s, 1354m,1250m, 1205m, 1173m, 1118m, 1033m, 977m, 936m, 759m, 739s, 621m, 597w,571w, 545s. ¹H-NMR (300 MHz, MeOH-d₄): 7.88-7.78 (m, 2H, H—C(4′)(Fmoc));7.71-7.61 (m, 2H, H—C(1′)(Fmoc)); 7.49-7.29 (m, 4H, H—C(3′)(Fmoc),H—C(2′)(Fmoc)); 6.08-5.68 (m, 1H, H—C(β)(Alloc)); 5.41-5.17 (m, 2H,H₂—C(γ)(Alloc); 4.58 (s, 2H, H₂C(α)(Alloc)); 4.74-4.17 (m, 5H,H₂-(10′)(Fmoc), H—C(9′)(Fmoc), H—C(4), H—C(2)); 3.94-3.73 (m, 1H,H—C(5)); 3.41-3.26 (m, 1H, H—C(5)); 2.74-2.54 (m, 1H, H—C(3)); 2.12-1.92(m, 1H, H—C(3)). ESI-MS (DCM+MeOH): 459.3 ([M+Na]⁺); 437.3 ([M+H]⁺).

[1138] 2.2.(2R,4S)-4-[(Allyloxy)carbonylamino]-1-((9H-fluoren-9-yl)methoxycarbonyl]-proline(217)

[1139] i: A solution of acetic anhydride (1.02 kg, 5.3eq, 10 mol) inglacial acetic acid (3 l) was heated to 50° C. and(2S,4R)-4-hydroxyproline (208) (247 g, 1.88 mol) was added in oneportion. The solution was refluxed for 5.5 h., cooled to roomtemperature and the solvent was removed under reduced pressure giving athick oil. The oil was then dissolved in 2N hydrochloric acid (3.5 l)and heated to reflux for 4 h and treated with charcoal and filteredthrough Celite. As the solution was evaporated, white needles formed,which were filtered. The product was dried at high vacuum:(2R,4R)-4-hydroxyproline-hydrochloride (213) white cryst. needles (220.9g, 70%). M.p.: 117° C. [α_(D) ²⁰=+19.3° (c=1.04, water). IR (KBr): 3238s3017s, 2569m, 1712s, 1584m, 1376s, 1332m, 1255s, 1204m, 1181w, 1091w,1066w, 994w, 725m, 499s. ¹H-NMR (600 MHz, MeOH-d₄): 9.64 (s, 1H, H—N);8.89 (s, 1H, H—N); 4.55-4.53 (m, 1H, H—C(4)); 4.51 (dd, J=10.4, 3.6 Hz,1H, H—C(2)); 3.44-3.35 (m, 2H, H₂—C(5)); 2.54-2.48 (m, 1H, H—C(3));2.40-2.34 (m, 1H, H—C(3)). ¹³C-NMR (150 MHz, MeOH-d₄): 171.9 (s, COOH);70.3 (d, C(4)); 59.6 (d, C(2)); 55.0 (t, C(5)); 38.5 (t, C(3)). EI-MS(NH₃): 132.1 ([M-Cl]⁺). The filtrate was further concentrated to give anadditional 59.5 g (19%)

[1140] ii,iii: To a solution of 213 (30 g, 0.18 mol) in abs. methanol(550 ml) was added dropwise at 0° C. thionyl chloride (38 ml, 2.5 eq,0.45 mol). The solution refluxed for 3 h under nitrogen atmosphere. Thesolution was evaporated and the ester hydrochloride precipitated byadding diethylether. After filtration the white solid was washed withdiethylether and dried at high vacuum: (2R,4R)-4-hydroxyprolinemethylester-hydrochloride white solid (29 g, 89%). [α]_(D) ²⁰=+8.6°(c=0.873, MeOH). IR (KBr): 3388s (br.), 2980s (r.), 1730s, 1634m, 1586s,1384s, 1248s, 1095s, 1064s, 1030m, 877m. ¹H-NMR (300 MHz, MeOH d):4.59-4.44 (m, 2H, H—C(4), H—C(2)); 3.81 (s, 3H, H₃C-0); 3.37-3.31 (m,2H, H₂—C(5)); 2.50-2.37 (m, 1H, H—C(3)), 2.37-2.27 (m, 1H, H—C(3)).“³C-NMR (75 MHz, MeOH-4): 170.9 (s, COOMe); 70.2 (d, C(4)); 59.8 (d,C(2)); 55.1 (t, C(5));)); 54.1 (q, C(Me)); 38.4 (1, C(3)). EI-MS (NH₃):146.1 ([M-Cl]⁺).

[1141] 10 g (55 mmol) of the above intermediate was dissolved in CH₂Cl₂(100 ml), cooled to 0° C. and triethylamine (15.2 ml, 2 eq, 0.11 mol)was added dropwise. Then di-tert.-butyldicarbonate (18.0 g, 1.5 eq, 83mmol) in CH₂Cl₂ (10 ml) and 4-N,N-dimethylaminopyridine (0.67 g, 0.1 eq,5 mmol) were added and the solution was stirred at RT overnight. Thesolution was washed with 1M aq. citric acid solution and sat. aqueousNaHCO₃ solution, dried (Na₂SO₄), the solvents evaporated and dried athigh vaccum:(2R,4R)₄-hydroxy-1-[(tert-butoxy)-carbonyl]prolinemethylester (214) as awhite solid (13 g, 97%). [α]_(D) ²⁰=+13.0 (c=1.06, CHCl₃). IR (KBr):3466s (br.), 2985s, 2930m, 1729s, 1679s, 1424s, 1283m, 1262m, 1122s,1089s, 969m, 770m. ¹H-NMR (300 MHz, CDCl₃): 4.43-4.26 (m, 2H, H—C(4),H—C(2)); 3.80+3.79 (2s, 3H, H₃C—O)); 3.76-3.47 (m, 2H, H₂—C(5));2.44-2.24 (m, 1H, H—C(3)); 2.16-2.03 (m, 1H, H—C(3)); 1.47+1.43 (2s, 9H,tBu). ESI-MS: 268.1 ([M+Na]⁺).

[1142] iv,v: 214 (12.2 g, 50 mmol) was dissolved in CH₂Cl₂ (130 ml),cooled to 0° C. and 4-nitrobenzenesulfonyl chloride (14.3 g, 1.3 eq, 65mmol) and Et₃N (10.3 ml, 1.5 eq, 75 mmol) were added The reactionmixture was stirred overnight and gradually brought to room temperature.The solution was washed with 1N hydrochloric acid and saturated aqueousNaHCO₃ solution, dried (Na₂SO₄), the solvents were evaporated and thecrude product was purified by filtration on silica gel with(2:1)-mixture of hexane/AcOEt: 18 g (84%). The product was thenrecrystallized from hexane/AcOEt:(2R,4R)[(p-nitrobenzyl)sulfonyloxy]-1-[(tert-butoxy)carbonyl]proline-methylesteras white crystals (13.7 g, 64%). TLC (hexane/AcOEt 1:1): R_(f)0.76.M.p.: 113-115° C. [α]_(D) ²⁰=+21.6° (c=0.924, CHCl₃). IR (KBr): 3112s(br.), 2981s, 2955s, 2882m, 1755s, 1683s, 1532s, 1413s, 1375s, 1348s,1192s, 928s, 911s, 759m, 745s, 610s. ¹H-NMR (600 MHz, CDCl₃): 8.45-8.35(m, 2H, H—C(Nos)); 8.15-8.06 (m, 2H, H—C(Nos)); 5.27-5.16 (m, 1H,H—C(4)); 4.53-4.32 (m, 1H, H—C(2)); 3.75-3.60 (m, 5H, H₂—C(5), H₃C—O);2.59-2.35 (m, 2H, H₂C(3)); 1.42+1.39 (2s, 9H, tBu). “³C-NMR (150 MHz,CDCl₃): 171.8+171.6 (s, COOMe); 153.8+153.4 (s, COOtBu); 151.0+142.6 (s,C(Nos)); 129.2+124.7 (d, C(Nos)); 81.0 (s, C-tBu); 80.8+79.7 (d, C(4));57.4+57.1 (d, C(2)); 52.6+52.5+52.3+51.8 (t, C(5), q, Me); 37.2+36.3 (t,C(3)); 28.5+28.3 (q, tBu). ESI-MS (DCM+MEOH+NaI): 453.2 ([M+Na]⁺).

[1143] 13 g (30 mmol) of the above intermediate was dissolved in DMF(200 ml), heated to 40° C. and sodium azide (14.3 g, 6 eq, 180 mmol) wasadded and the reaction mixture stirred over-night. The reaction mixturewas evaporated and the residue suspended in diethylether. The suspensionwas filtered, the filtrate washed with water and the organic phasedried(Na₂SO₄).

[1144] The solvent was evaporated and the product dried at high vacuum:(2R,4S)-4azido-1-[(tert-butoxy)carbonyl]prolinemethylester (215) as ayellow oil (8.15 g, 99%). [α]_(D) ²⁰=+42.8° (c=1.05, CHCl₃). ¹H-NMR (300MHz, CDCl₃): 4.58-4.37 (n, 1H, H—C(2)); 4.34-4.23 (m, 1H, H—C(4));3.92-3.51 (m, 5H, H₂—C(5), H₃C—O); 2.52-2.33 (m, 1H, H—C(3)); 2.33-2.20(m, 1H, H—C(3)); 1.56+1.51 (2s, 9H, tBu). CI-MS (NH₃): 288.2 ([M+NH₄]⁺;271.1 ([M+H]⁺).

[1145] vi,vii: 215 (8 g, 30 mmol) was dissolved in a (3:1)-mixture ofdioxane/water (400 ml), cooled to 0° C. and SnCl₂ (22.4 g, 4 eq, 120mmol) was added and the reaction mixture stirred for 30 min. at 0°,gradually warmed to room temperature and stirred for another 5h. Afteradjusting the pH of the solution to 8 with solid NaHCO₃, allylchloroformate (15.7 ml, 5 eq, 150 mmol) was added. The reaction mixturewas stirred overnight at room temperature, evaporated and extracted withAcOEt and the organic phase washed with brine. After drying the organicphase (Na₂SO₄), the solvent was evaporated and the product dried at highvacuum: (2R,4S)-4-[(Allyloxy)carbonylamino]-1-[(tert-butoxy)carbonyl]proline-methylester as a clear thick oil (216) (8.7 g, 89%). [α]_(D)²⁰=+41.9° (c=0.928, CHCl₃). ¹H-NNR (300 MHz CDCl₃): 5.98-5.87 (m, 1H,H—C(β)(Alloc)); 5.34-5.02 (m, 2H, H₂—C(γ)(Alloc); 4.62-4.49 (m, 2H,H₂—C(α)(Alloc)); 4.4-14.23 (m, 2H, H—C(4), H—C(2)); 3.82-3.66 (m, 4H,H—C(5), H₃C—O); 3.43-3.20 (m, 1H, H—C(5)); 2.33-2.07 (m, 2H, H₂—C(3));1.43+1.39 (2s, 9H, tBu). CI-MS (NH₃): 329.1 ([M+H]⁺).

[1146] vii-x: 216 (8.4 g, 25 mmol) was dissolved in (4:1)-mixture ofmethanol/water (100 ml) at room temperature, LiOH (2.2 g, 2 eq, 50 mmol)added and the solution stirred overnight. Methanol was evaporated andthe residue poured onto 1N hydrochloric acid (100 ml) and extracted withAcOEt. The solvent was removed and the residue dissolved in(1:1)-mixture of TFA/CH₂Cl₂ (200 ml) and stirred for 2h. The solventswere evaporated and the product dried at high vaccum:(2R,4R)-4-[(Allyloxy)carbonylamino]proline as a clear oil (5.2 g, 96%)¹H-NMR (300 MHz MeOH-d₄): 6.04-5.88 (m, 1H, H₂—C(β)(Alloc)); 5.38-5.19(m, 2H, H₂—C(γ)(Alloc); 4.64-4.54 (m, 3H, H₂C(α)(Alloc), H—C(4));4.39-4.22 (m, 1H, H—C(2)); 3.71-3.60 (m, 1H, H—C(5)); 3.45-3.32 (m, 1H,H—C(5)); 2.51-2.41 (m, 2H, H₂C(3)). CI-MS (NH₃): 215.1 ([M+H]4).

[1147] 200 mg (0.86 mmol) of the above intermediate and9-fluorenylmethoxycarbonylsuccinimide (440 mg, 1.5 eq, 1.3 mmol) weredissolved in CH₂Cl₂ (10 ml) and DIEA (466 μl, 4 eq, 3.44 mmol) wasadded, and the solution stirred overnight at room temperature. Thesolvent was removed and the residue dissolved in AcOEt, washed with 1Nhydrochloric acid dried (Na₂SO₄). After evaporation, the crude productwas purified by filtration over silica gel with first a gradient of(3:1) hexane/AcOEt to AcOEt. The solvent was coevaporated with CH₂Cl₂and the product dried at high vacuum:(2R,4S)-4[(Allyloxy)carbonylamino]-1-[(9H-fluoren-9-yl)methoxycarbonyl]-proline(217) white solid (90 mg, 33%) [α]_(D) ²⁰=+29.3° (c=1.08, CHCl₃). IR(KBr): 3314s (br.), 3066s (br.), 2952s (br.), 1708s (br.), 1536m, 1424s,1353s, 1126m, 1030 in, 909m, 759m, 738s, 620m. ¹H-NMR (300 MHz, CDCl₃):8.74 (s, 1H, H—N); 7.79-7.66 (m, 2H, H—C(4′)(fmoc)); 7.62-7.49 (m, 2H,H—C(1′)(fmoc)); 7.44-7.22 (m, 4H, H—C(3′)(fmoc), H—C(2′)(fmoc));6.03-5.74 (m, 1H, H—C(β)(Alloc)); 5.41-5.07 (m, 2H, H₂—C(γ)(Alloc);4.74-4.17 (m, 7H, H₂—C(10′)(fmoc), H—C(9′)(fmoc), H—C(4), H—C(2),H₂—C(α)(Alloc)); 3.91-3.76 (m, 1H, H—C(5)); 3.48-3.25 (m, 1H, H—C(5));2.45-2.08 (m, 2H, H₂—C(3)). ESI-MS (MeOH): 437.3 ([M+H]⁺); ESI-MS(MeOH+Na): 459.1 ([M+Na]⁺).

[1148] 2.3. Starting from derivatives 210 and 215 the key precursors219a-u and 221a-u can be prepared according to Scheme 44.

[1149] R⁶⁴: n-hexyl (219a, 221a); n-heptyl (219b, 221b);4-(phenyl)benzyl (219c, 221c); diphenylmethyl (219d, 221d);3-amino-propyl (219e, 221e); 5-amino-pentyl (219f, 221f); methyl (219g,221g); ethyl (219h, 221h); isopropyl (2191, 221i); isobutyl (219k,221k); n-propyl (2191, 2211); cyclohexyl (219m, 221m); cyclohexylmethyl(219n, 221n); n-butyl (219o, 221o); phenyl (219p, 221p); benzyl (219q,221q); (3-indolyl)methyl (219r, 221r); 2-(3-indolyl)ethyl (219s, 221s);(4phenyl)phenyl (219t, 221t); n-nonyl (219u, 221u).

[1150] i,ii: Typical Procedures:

[1151] To a solution of 78 mmol of azides 210 and 215 in a (3:1)-mixtureof dioxane/water (500 ml) was added at 0° C. SnCl₂ (59.2 g, 4 eq, 0.31mol) and the solution was stirred for 30 minutes. The reaction mixturewas gradually warmed up to room temperature and stirred for another 5hours. After adjusting the pH to 8 with solid NaHCO₃, the reactionmixture was extracted with CH₂Cl₂, the organic fraction dried (MgSO₄),evaporated and the residue dried under reduced pressure. The residue wasdissolved in CH₂Cl₂ (300 ml), cooled to 4° with an ice bath, followed byaddition of DIEA (20.0 ml, 117 mmol) and a solution of the appropriateacid chloride R^(64′)COCl (101.0 mmol) in CH₂Cl₂ (50 ml) at 4° C. Thereaction mixture was stirred for 1 hour at 4° and for 18 hours at roomtemperature and extracted with HCl aq. (0.5N, 200 ml) and CH₂Cl₂. Theorganic fraction was dried (MgSO₄), evaporated and the residuechromatographed on SiO₂ with gradients of ethylacetate/hexane yielding218a-u and 220a-u, which were converted into the final products 219a-uand 221a-u as described for the conversion of 216 into 217. The overallyields were 50-60%.

[1152] Templates (b1):

[1153] Synthesis of(2S,6S,8aR)-8a-{[(tert.-butyl)oxycarbonyl]methyl}perhydro-5,8-dioxo-{[(9H-fluoren-9-yl)methoxycarbonyl]amino}-pyrrolo[1,2-a]pyrazine-6-aceticacid (222):

[1154] To a stirred solution of 250 mg (0.414 mmol) of allyl{(2S,6S,8aR)-8a-[(tert.-butyl)oxycarbonyl]methyl}perhydro-5,8-dioxo-{[(9H-fluoren-9-yl)methoxycarbonyl]amino}-pyrrolo[1,2-a]pyrazin-6-acetatein a degassed mixture of dichloromethane/methanol (9:1, 3 ml) were addedunder argon 25 mg (0.0216mmol) of tetrakis(triphenylphosphine)palladium,0.05 ml of acetic acid and 0.025 ml of N-methylmorpholine. The reactionmixture was stirred for 48 hours at room temperature and poured ontowater and dichloromethane. The organic phase was dried (MgSO₄),evaporated and the residue chromatographed on SiO₂ withdichloromethane/methanol (9:1) to yield 180 mg (77%) of(25,6S,8aR)-8a-{[(tert.-butyl)oxycarbonyl]methyl}perhydro-5,8-dioxo-{[(9H-fluoren-9-yl)-methoxycarbonyl]amino}-pyrrolo[1,2-a]pyrazine-6-aceticacid (222) as a white powder.

[1155]¹H-NMR(300 MHz, DMSO-d₆): 8.30 (s, 1H); 7.88 (d, J=7.2, 2H); 7.67(d, J=7.4, 2H); 7.62 (br.s, 1H); 7.41 (t, J=7.2, 2H); 7.33 (t, J=7.4,2H); 4.35-4.2 (m, 5H); 3.55 (br.d, J=6.3, 2H); 2.8-2.55 (m, 3H);2.45-2.25 (m, 2H); 2.1-1.95 (m, 1H); 1.35 (s, 9H); MS(ESI): 586.1(M+Na)⁺, 564.1 (M+H)⁺.

[1156] Experimental procedure described in W. Bannwarth, A. Knierzinger,K. Müller, D. Obrecht, A. Trzeciak EP 0 592 791 A2, 1993.

[1157] 3. Biological Methods

[1158] 3.1. Preparation of the Peptides.

[1159] Lyophilized peptides were weighed on a Microbalance (Mettler MT5)and dissolved in sterile water containing 0.01% acetic acid Tachyplesinwas purchased from Bachem Ltd. (Bubendorf Switzerland).

[1160] 3.2. Antimicrobial Activity of the Peptides.

[1161] The antimicrobial activities of the peptides were determined bythe standard NCCLS broth microdilution method (see ref 1, below)examined in sterile 96-wells plates (Nunclon polystyrene microtiterplates) in a total volume of 100 μl. Innocula of the microorganisms wereprepared with 0.5 Mcfarland standard and then diluted intoMueller-Hinton (MH) broth to give appr. 10⁶ colony forming units(CFU)/ml for bacteria or 5×10³ CFU/ml for Candida. Aliquots (50 μl) ofthe innocula were added to 50 μl of MH broth containing the peptide inserial twofold dilutions. The microorganisms used were Escherichia coli(ATCC 25922), Pseudomnonas aeruginosa (P. aeruginosa) (ATCC 27853),Stahylococcus aureus (ATCC 29213 and ATCC 25923) and Candida albicans. Aselected number of peptides were screened for activity against a largerpanel of gram-negative strains. These strains were; Escherichia coliATCC 43827 and clinical isolates of Pseudomonas (P. aeruginosa V0714482, P. aeruginosa 15288, P. aeruginosa V02 15328 and P. aeruginosaV09 16085) and Acinetobacter (Acinetobacter V04 19905/1, AcinetobacterV12 21143/1 and Acinetobacter V12 21193/1). Antimicrobial activities ofthe peptides were expressed as the minimal inhibitory concentration(MIC) in jig/min at which no visible growth was observed after 18-20hours of incubation of the microtiter plates at 37° C.

[1162] 3-3. Antimicrobial Activity of the Peptides in 1% Salt

[1163] Salt sensitivity of the peptides was tested by the microtiterserial dilution assay as described above. Only MH broth was replaced byMH broth containing 1% NaCl.

[1164] 3.4. Antimicrobial Activity of the Peptides in Human Serum

[1165] Serum binding of the peptides was tested by microtiter serialdilution assay as described above. Only MH broth was replaced by MHbroth containing 90% human serum (BioWhittaker).

[1166] 3.5. Hemolysis

[1167] The peptides were tested for their hemolytic activity againsthuman red blood cells (hRBC). Fresh hRBC were washed three times withphosphate buffered saline (PBS) by centrifugation for 10 min at 2000×g.Peptides at a concentration of 100 μg/ml were incubated with 20% v/vhRBC for 1 hour at 37° C. The final erythrocyte concentration was appr.0.9×10⁹/ml. A value of 0% resp. 100% cell lysis was determined byincubation of the hRBC in the presence of PBS alone and resp. 0.1%Triton X-100 in H₂O. The samples were centrifuged and the supernatantwas 20 fold diluted in PBS buffer and the optical density (OD) of thesample at 540 nM was measured. The 100% lysis value (OD₅₄₀H₂O) gave anOD of approximately 1.6-2.0. Percent hemolysis was calculated asfollows: (OD₅₄₀peptide/OD₅₄₀H₂O)×100%.

[1168] 3.6. Cytotoxicity Assay

[1169] The cytotoxicity of the peptides to HELA cells (Acc57) and MCF-7cells (Acc115) was determined using the MTT reduction assay (see ref 2and 3, below). Briefly the method is as follows; HELA cells and MCF-7cells were grown in RPMI1640 plus 5% fetal calf serum in microtiterplates for 48 hours at 37° C. at 5% CO₂. The total number of cells wasfinally 10⁶ cells per well. The supernatant of the cell cultures wasdiscarded and fresh RPMI1640 medium containing 5% fetal calf serum andthe peptides in serial dilutions of 12.5, 25 and 50 μg/ml were pipetedinto the wells. Each peptide concentration was assayed in triplicate.Incubation of the cells was continued for 20-24 hours at 37° C. at 5%CO₂. Wells were then washed three times with fresh RPMI medium andfinally 100 μl MTT reagent (0.5 mg/ml in RPMI1640) was added to eachwell. This was incubated at 37° C. for 2 hours and subsequently thewells were washed once with PBS. 100 μl isopropanol was added to eachwell and the absorbance at 595 nm of the solubilized product wasmeasured (OD₅₉₅peptide). The 100 percent growth value (OD₅₉₅Medium) wasdetermined from wells containing HELA or MCF-7 cells with RPMI1640 plus5% fetal calf serum but no peptides. The zero percent growth value(OD₅₉₅Empty well) was extracted from wells that did not contain HELA orMCF-7 cells. The percentage MTT reduction for a certain peptideconcentration was calculated as follows: (OD₅₉₅peptide-OD₅₉₅Emptywell)/(OD₅₉₅Medium-OD₅₉₅Empty well)×100% and was plotted for eachpeptide concentration. The EC₅₀ of a peptide is defined as theconcentration at which 50% inhibition of MIT reduction was observed andwas calculated for each peptide.

REFERENCES

[1170] 1. National Committee for Clinical Laboratory Standards. 1993.Methods for dilution antimicrobial susceptibility tests for bacteriathat grow aerobically, 3rd ed. Approved standard M7-A3. NationalCommittee for Clinical laboratory standards, Villanova, Pa.

[1171] 2. Mossman T. J Immunol Meth 1983, 65, 55-63

[1172] 3. Berridge M V, Tan A S. Archives of Biochemistry & Biophysics1993, 303, 474-482

[1173] 3.7 Results TABLE 8 Minimal inhibitory concentrations (MIC inμg/ml) and percentage hemolyses at a concentration of 100 μg/ml ofpeptide Pseudomonas Staphylococcus Staphylococcus Escherichia putidaaureus aureus coli ATCC ATCC ATCC ATCC Candida Hemolyses Ex. 25922 2785329213 25923 albicans hRBC 11 25 100 100 100 100 0.2 36 25 25 25 50 250.5 40 25 50 25 50 25 1.2 59 4.7 50 25 50 25 3.0 63 6.2 50 12.5 25 12.53.0 71 12.5 100 12.5 12.5 50 1.2 87 6.2 6.2 9.4 9.4 12.5 3.7 101 12.550 >50 >50 50 0.2 103 9.4 25 25 25 12.5 18.3 105 6.2 9.4 12.5 6.2 6.231.0 106 12.5 6.2 25 12.5 12.5 1.4 107 25 6.2 12.5 9.4 12.5 10.4 109 5025 50 50 12.5 3.2 112 25 50 25 25 25 2.6 113 50 100 100 100 100 9.2 11950 25 >100 100 50 3.5 120 18.8 9.4 18.8 9.4 12.5 1.1 121 25 25 6.2 6.26.2 7.1 126 25 25 25 50 25 2.6 128 6.2 12.5 6.2 6.2 12.5 13.9 133 6.26.2 12.5 25 12.5 1.1 134 12.5 6.2 12.5 25 12.5 1.2 137 25 6.2 6.2 6.26.2 3.1 139 25 6.2 12.5 9.4 6.2 3.5 140 12.5 6.2 12.5 12.5 6.2 2.7 14125 12.5 25 25 12.5 2.0 142 25 12.5 50 25 12.5 2.3 146 12.5 12.5 25 12.56.2 30.1 147 50 25 25 25 12.5 1.9 148 25 12.5 12.5 9.4 6.2 3.9 150 2512.5 12.5 12.5 12.5 29.3 151 50 50 100 50 25 4.9 152 25 25 50 25 12.529.1 154 12.5 12.5 25 12.5 12.5 31.5 155 6.2 12.5 6.2 12.5 6.2 10.1 15650 12.5 12.5 6.2 12.5 35.2 158 12.5 6.2 12.5 12.5 12.5 10.5 159 12.512.5 12.5 12.5 12.5 21.7 161 25 12.5 6.2 6.2 12.5 3.7 163 12.5 12.5 12.512.5 12.5 24.6 165 6.2 12.5 25 18 12.5 0.2 168 12.5 12.5 25 25 12.5 1.1172 6.2 25 25 25 12.5 1.0 173 12.5 25 6.2 12.5 12.5 27.4 175 12.5 6.212.5 12.5 12.5 2.4 177 25 12.5 25 25 12.5 4.1 182 12.5 6.2 6.2 25 12.56.2 185 12.5 6.2 6.2 6.2 12.5 17.6 186 6.2 3.1 6.2 6.2 6.2 11.5 187 12.5100 50 100 25 0.3 197 12.5 3.1 6.2 6.2 6.2 3.4 203 6.2 6.2 6.2 6.2 6.233.0 205 6.2 6.2 12.5 6.2 6.2 27.0 206 6.2 6.2 12.5 12.5 6.2 8.5 207 5050 25 50 25 0.1 208 12.5 6.2 6.2 6.2 12.5 18.4 209 12.5 6.2 12.5 12.518.8 6.4 210 12.5 6.2 25 25 25 1.9 214 12.5 6.2 12.5 12.5 12.5 1.0 21612.5 6.2 12.5 25 12.5 1.4 217 18.8 6.2 12.5 25 12.5 1.7 218 25 6.2 25 2525 2.2 219 12.5 12.5 50 50 25 2.6 220 12.5 18.8 25 25 12.5 2.3 222 12.56.2 12.5 12.5 6.2 2.2 223 6.2 12.5 12.5 25 12.5 2.7 224 6.2 12.5 18.8 2512.5 3.7 225 6.2 12.5 12.5 25 12.5 4.4 228 12.5 6.2 6.2 6.2 12.5 6.3 22912.5 6.2 3.1 6.2 6.2 4.8 230 6.2 6.2 6.2 9.4 12.5 1.7 232 6.2 12.5 9.46.2 9.4 1.5 233 9.4 12.5 9.4 6.2 12.5 37 234 6.2 12.5 6.2 3.1 12.5 33.9242 6.2 12.5 6.2 12.5 12.5 19.4 244 3.1 12.5 6.2 6.2 12.5 22.7 250 6.26.2 12.5 12.5 12.5 0.7 251 6.2 9.4 6.2 12.5 12.5 4.1 254 12.5 6.2 6.212.5 12.5 11.7 256 3.1 3.1 6.2 6.2 6.2 2.7 257 6.2 6.2 6.2 6.2 25 19.6258 6.2 6.2 6.2 6.2 12.5 23.6 259 6.2 6.2 6.2 6.2 12.5 18.0 267 12.5 6.26.2 12.5 12.5 3.4 277 25 18.8 3.1 6.2 6.2 12.7 278 12.5 25 50 50 50 5.3279 12.5 12.5 50 50 50 4.9 280 12.5 12.5 50 100 25 1.8 281 12.5 4.7 100100 50 1.1 282 12.5 12.5 25 50 25 1.6 283 12.5 4.7 100 100 50 1.0 2846.2 1.6 12.5 12.5 12.5 0.7 287 25 50 12.5 25 25 28.5 288 25 1.5 100 100100 1.1 289 50 3.1 25 25 25 1.7 292 25 6.2 50 100 25 1.3 293 25 12.5 100100 100 1.3 294 25 3.1 100 100 50 1.5 295 25 6.5 50 100 50 2.0 296 12.56.2 25 50 25 1.9 297 25 3.1 100 100 50 0.9 298 25 3.1 100 200 50 1.0 29950 6.2 25 100 50 2.5 300 25 12.5 12.5 25 50 6.5 301 25 50.0 50.0 25 50.00.5 302 6.2 3.1 3.1 6.2 6.2 3.4

[1174] TABLE 9 Minimal inhibitory concentration (MIC in μg/ml) inMueller-Hinton broth containing 1% NaCl Escherichia PseudomonasStaphylococcus Staphylococcus coli putida aureus aureus ATCC ATCC ATCCATCC Candida Ex. 25922 27853 29213 25923 albicans 106 100 50 100 100 100197 12.5 6.2 18.8 12.5 12.5 230 25 50 50 50 18.8 250 12.5 50 100 50 50229 50 18.8 25 25 12.5 256 6.2 6.2 25 25 25

[1175] Several compounds which showed a preference towards Gram-negativebacteria were tested against several pseudomonas strains as shown inTable 10. TABLE 10 Minimal inhibitory concentrations (MIC in μg/ml)against pseudomonas strains MIC (□g/ml) ex. 197 ex. 284 ex. 283 ex. 288ex. 289 ex. 292 ex. 296 ex. 297 ex. 298 Escherichia coli ATCC 25922 12.56.2 25 25 25 25 12.5 25 25 Escherichia coli ATCC 43827 12.5 12.5 12.512.5 25 25 12.5 12.5 12.5 P. aeruginosa ATCC 278853 3.1 1.6 3.1 3.1 6.26.2 3.1 3.1 3.1 P. aeruginosa VO7 14482 12.5 3.1 4.7 3.1 6.2 12.5 12.54.7 3.1 P. aeruginosa 15288 12.5 3.1 2.5 6.2 6.2 12.5 12.5 6.2 4.7 P.aeruginosa V02 15328 12.5 3.1 6.2 3.1 6.2 12.5 12.5 6.2 3.1 P.aeruginosa V09 16085 9.4 1.6 3.1 6.2 6.2 6.2 6.2 3.1 3.1 AcinetobacterV04 19905/1 12.5 6.2 6.2 6.2 12.5 12.5 6.2 6.2 6.2 Acinetobacter V1221143/1 12.5 3.1 6.2 6.2 6.2 6.2 6.2 6.2 9.4 Acinetobacter V12 21193/112.5 3.1 3.1 6.2 3.1 6.2 3.1 6.2 6.2

[1176] TABLE 11 Anticancer activity (EC₅₀-values) in μg/ml ExampleHemolysis ex. Hela (μg/ml) MCF (μg/ml) hRBC 80 337 nd nd 106 43 39 1.4170 24 41 nd 197 20 23 3.4 229 13 25 4.8 230 23 32 1.7 285 11 11 4.2 286nd 23 17.1

[1177]

0 SEQUENCE LISTING <160> NUMBER OF SEQ ID NOS: 304 <210> SEQ ID NO 1<211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Description of ArtificialSequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE<222> LOCATION: (9)..(9) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 1 Tyr Val Arg Arg Arg Phe Leu Val Xaa Pro 1 5 10 <210> SEQ IDNO 2 <211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <223> OTHER INFORMATION: Description ofArtificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (9)..(9) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 2 Tyr Val Arg Lys Gly Phe Leu Val Xaa Pro 1 5 10<210> SEQ ID NO 3 <211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Descriptionof Artificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (9)..(9) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 3 Trp Val Arg Lys Gly Phe Leu Trp Xaa Pro 1 5 10<210> SEQ ID NO 4 <211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Descriptionof Artificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (9)..(9) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 4 Tyr Val Arg Arg Arg Trp Leu Val Xaa Pro 1 5 10<210> SEQ ID NO 5 <211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Descriptionof Artificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (9)..(9) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 5 Tyr Val Tyr Arg Arg Phe Leu Val Xaa Pro 1 5 10<210> SEQ ID NO 6 <211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Descriptionof Artificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (9)..(9) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 6 Lys Val Tyr Arg Arg Phe Leu Val Xaa Pro 1 5 10<210> SEQ ID NO 7 <211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Descriptionof Artificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (9)..(9) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 7 Lys Val Tyr Lys Gly Phe Leu Trp Xaa Pro 1 5 10<210> SEQ ID NO 8 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Descriptionof Artificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (10)..(10) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 8 Arg Phe Leu Arg Arg Arg Leu Phe Arg Xaa Pro 1 510 <210> SEQ ID NO 9 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Descriptionof Artificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (10)..(10) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 9 Arg Tyr Leu Arg Arg Arg Leu Tyr Arg Xaa Pro 1 510 <210> SEQ ID NO 10 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Descriptionof Artificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (10)..(10) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 10 Arg Phe Phe Arg Arg Arg Leu Phe Arg Xaa Pro 1 510 <210> SEQ ID NO 11 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Descriptionof Artificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (10)..(10) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 11 Arg Tyr Tyr Arg Arg Arg Leu Tyr Arg Xaa Pro 1 510 <210> SEQ ID NO 12 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Descriptionof Artificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (10)..(10) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 12 Leu Phe Phe Arg Arg Arg Leu Phe Arg Xaa Pro 1 510 <210> SEQ ID NO 13 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Descriptionof Artificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (10)..(10) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 13 Leu Tyr Tyr Arg Arg Arg Leu Tyr Arg Xaa Pro 1 510 <210> SEQ ID NO 14 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Descriptionof Artificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (10)..(10) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 14 Arg Phe Leu Phe Arg Arg Leu Leu Arg Xaa Pro 1 510 <210> SEQ ID NO 15 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Descriptionof Artificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (10)..(10) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 15 Arg Tyr Leu Tyr Arg Arg Leu Leu Arg Xaa Pro 1 510 <210> SEQ ID NO 16 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Descriptionof Artificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (10)..(10) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 16 Leu Phe Leu Phe Arg Arg Leu Phe Arg Xaa Pro 1 510 <210> SEQ ID NO 17 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Descriptionof Artificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (10)..(10) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 17 Leu Tyr Leu Tyr Arg Arg Leu Tyr Arg Xaa Pro 1 510 <210> SEQ ID NO 18 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Descriptionof Artificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (10)..(10) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 18 Arg Phe Leu Phe Arg Arg Leu Phe Leu Xaa Pro 1 510 <210> SEQ ID NO 19 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Descriptionof Artificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (10)..(10) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 19 Arg Tyr Leu Tyr Arg Arg Leu Tyr Leu Xaa Pro 1 510 <210> SEQ ID NO 20 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Descriptionof Artificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (10)..(10) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 20 Phe Leu Leu Phe Arg Arg Leu Phe Arg Xaa Pro 1 510 <210> SEQ ID NO 21 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Descriptionof Artificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (10)..(10) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 21 Tyr Leu Leu Tyr Arg Arg Leu Tyr Arg Xaa Pro 1 510 <210> SEQ ID NO 22 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Descriptionof Artificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (10)..(10) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 22 Arg Leu Leu Phe Arg Arg Leu Phe Phe Xaa Pro 1 510 <210> SEQ ID NO 23 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Descriptionof Artificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (10)..(10) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 23 Arg Leu Leu Tyr Arg Arg Leu Tyr Tyr Xaa Pro 1 510 <210> SEQ ID NO 24 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Descriptionof Artificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (10)..(10) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 24 Arg Phe Leu Arg Arg Phe Leu Phe Arg Xaa Pro 1 510 <210> SEQ ID NO 25 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Descriptionof Artificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (10)..(10) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 25 Arg Phe Leu Arg Arg Phe Phe Leu Arg Xaa Pro 1 510 <210> SEQ ID NO 26 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Descriptionof Artificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (10)..(10) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 26 Arg Tyr Leu Arg Arg Tyr Tyr Leu Arg Xaa Pro 1 510 <210> SEQ ID NO 27 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Descriptionof Artificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (10)..(10) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 27 Leu Tyr Leu Arg Arg Tyr Leu Tyr Arg Xaa Pro 1 510 <210> SEQ ID NO 28 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Descriptionof Artificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (10)..(10) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 28 Leu Leu Phe Phe Arg Arg Leu Phe Arg Xaa Pro 1 510 <210> SEQ ID NO 29 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Descriptionof Artificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (10)..(10) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 29 Leu Leu Tyr Tyr Arg Arg Leu Tyr Arg Xaa Pro 1 510 <210> SEQ ID NO 30 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Descriptionof Artificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (10)..(10) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 30 Arg Leu Phe Phe Arg Arg Leu Phe Leu Xaa Pro 1 510 <210> SEQ ID NO 31 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Descriptionof Artificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (10)..(10) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 31 Arg Leu Tyr Tyr Arg Arg Leu Tyr Leu Xaa Pro 1 510 <210> SEQ ID NO 32 <211> LENGTH: 12 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Descriptionof Artificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (11)..(11) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 32 Arg Phe Leu Phe Arg Arg Arg Leu Phe Arg Xaa Pro1 5 10 <210> SEQ ID NO 33 <211> LENGTH: 12 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (11)..(11) <223> OTHERINFORMATION: Xaa is D-Pro <400> SEQUENCE: 33 Arg Tyr Leu Tyr Arg Arg ArgLeu Tyr Arg Xaa Pro 1 5 10 <210> SEQ ID NO 34 <211> LENGTH: 12 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Description of Artificial Sequence: Cyclic peptide <220>FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (11)..(11) <223>OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 34 Arg Phe Phe Phe ArgArg Arg Leu Leu Arg Xaa Pro 1 5 10 <210> SEQ ID NO 35 <211> LENGTH: 12<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: Description of Artificial Sequence: Cyclic peptide<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (11)..(11)<223> OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 35 Arg Tyr Tyr TyrArg Arg Arg Leu Leu Arg Xaa Pro 1 5 10 <210> SEQ ID NO 36 <211> LENGTH:12 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Cyclicpeptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:(11)..(11) <223> OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 36 ArgLeu Phe Phe Arg Arg Arg Leu Phe Arg Xaa Pro 1 5 10 <210> SEQ ID NO 37<211> LENGTH: 12 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Description of ArtificialSequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE<222> LOCATION: (11)..(11) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 37 Leu Tyr Leu Tyr Arg Arg Arg Leu Tyr Arg Xaa Pro 1 5 10<210> SEQ ID NO 38 <211> LENGTH: 12 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Descriptionof Artificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (11)..(11) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 38 Arg Phe Leu Phe Arg Arg Arg Leu Phe Leu Xaa Pro1 5 10 <210> SEQ ID NO 39 <211> LENGTH: 12 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (11)..(11) <223> OTHERINFORMATION: Xaa is D-Pro <400> SEQUENCE: 39 Arg Tyr Leu Tyr Arg Arg ArgLeu Tyr Leu Xaa Pro 1 5 10 <210> SEQ ID NO 40 <211> LENGTH: 12 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Description of Artificial Sequence: Cyclic peptide <220>FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (11)..(11) <223>OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 40 Leu Leu Phe Phe ArgArg Arg Leu Phe Arg Xaa Pro 1 5 10 <210> SEQ ID NO 41 <211> LENGTH: 12<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: Description of Artificial Sequence: Cyclic peptide<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (11)..(11)<223> OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 41 Arg Leu Phe PheArg Arg Arg Leu Phe Leu Xaa Pro 1 5 10 <210> SEQ ID NO 42 <211> LENGTH:12 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Cyclicpeptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:(11)..(11) <223> OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 42 LeuTyr Tyr Tyr Arg Arg Arg Leu Leu Arg Xaa Pro 1 5 10 <210> SEQ ID NO 43<211> LENGTH: 12 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Description of ArtificialSequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE<222> LOCATION: (11)..(11) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 43 Arg Phe Phe Phe Arg Arg Arg Leu Leu Leu Xaa Pro 1 5 10<210> SEQ ID NO 44 <211> LENGTH: 12 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Descriptionof Artificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (11)..(11) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 44 Arg Tyr Tyr Tyr Arg Arg Arg Leu Leu Leu Xaa Pro1 5 10 <210> SEQ ID NO 45 <211> LENGTH: 12 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (11)..(11) <223> OTHERINFORMATION: Xaa is D-Pro <400> SEQUENCE: 45 Arg Leu Leu Phe Arg Gly ArgPhe Phe Arg Xaa Pro 1 5 10 <210> SEQ ID NO 46 <211> LENGTH: 12 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Description of Artificial Sequence: Cyclic peptide <220>FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (11)..(11) <223>OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 46 Arg Leu Leu Tyr ArgGly Arg Tyr Tyr Arg Xaa Pro 1 5 10 <210> SEQ ID NO 47 <211> LENGTH: 12<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: Description of Artificial Sequence: Cyclic peptide<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (11)..(11)<223> OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 47 Arg Phe Phe PheArg Gly Arg Leu Leu Arg Xaa Pro 1 5 10 <210> SEQ ID NO 48 <211> LENGTH:12 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Cyclicpeptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:(11)..(11) <223> OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 48 ArgTyr Tyr Tyr Arg Gly Arg Leu Leu Arg Xaa Pro 1 5 10 <210> SEQ ID NO 49<211> LENGTH: 12 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Description of ArtificialSequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE<222> LOCATION: (11)..(11) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 49 Leu Phe Leu Phe Arg Gly Arg Leu Phe Arg Xaa Pro 1 5 10<210> SEQ ID NO 50 <211> LENGTH: 12 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Descriptionof Artificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (11)..(11) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 50 Leu Tyr Leu Tyr Arg Gly Arg Leu Tyr Arg Xaa Pro1 5 10 <210> SEQ ID NO 51 <211> LENGTH: 12 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (11)..(11) <223> OTHERINFORMATION: Xaa is D-Pro <400> SEQUENCE: 51 Arg Phe Leu Phe Arg Gly ArgLeu Phe Leu Xaa Pro 1 5 10 <210> SEQ ID NO 52 <211> LENGTH: 12 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Description of Artificial Sequence: Cyclic peptide <220>FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (11)..(11) <223>OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 52 Arg Tyr Leu Tyr ArgGly Arg Leu Tyr Leu Xaa Pro 1 5 10 <210> SEQ ID NO 53 <211> LENGTH: 12<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: Description of Artificial Sequence: Cyclic peptide<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (11)..(11)<223> OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 53 Leu Arg Phe PheArg Leu Arg Leu Phe Arg Xaa Pro 1 5 10 <210> SEQ ID NO 54 <211> LENGTH:12 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Cyclicpeptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:(11)..(11) <223> OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 54 LeuArg Tyr Tyr Arg Leu Arg Leu Tyr Arg Xaa Pro 1 5 10 <210> SEQ ID NO 55<211> LENGTH: 12 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Description of ArtificialSequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE<222> LOCATION: (11)..(11) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 55 Leu Leu Phe Phe Arg Gly Arg Leu Phe Arg Xaa Pro 1 5 10<210> SEQ ID NO 56 <211> LENGTH: 12 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Descriptionof Artificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (11)..(11) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 56 Leu Leu Tyr Tyr Arg Gly Arg Leu Tyr Arg Xaa Pro1 5 10 <210> SEQ ID NO 57 <211> LENGTH: 12 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (11)..(11) <223> OTHERINFORMATION: Xaa is D-Pro <400> SEQUENCE: 57 Arg Phe Leu Phe Arg Gly ArgPhe Arg Leu Xaa Pro 1 5 10 <210> SEQ ID NO 58 <211> LENGTH: 12 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Description of Artificial Sequence: Cyclic peptide <220>FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (11)..(11) <223>OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 58 Arg Tyr Leu Tyr ArgGly Arg Tyr Arg Leu Xaa Pro 1 5 10 <210> SEQ ID NO 59 <211> LENGTH: 13<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: Description of Artificial Sequence: Cyclic peptide<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (12)..(12)<223> OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 59 Arg Leu Phe LeuArg Arg Arg Phe Phe Arg Leu Xaa Pro 1 5 10 <210> SEQ ID NO 60 <211>LENGTH: 13 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:Cyclic peptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>LOCATION: (12)..(12) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 60 Arg Leu Tyr Leu Arg Arg Arg Tyr Tyr Arg Leu Xaa Pro 1 5 10<210> SEQ ID NO 61 <211> LENGTH: 13 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Descriptionof Artificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (12)..(12) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 61 Leu Leu Phe Leu Arg Arg Arg Phe Phe Arg Arg XaaPro 1 5 10 <210> SEQ ID NO 62 <211> LENGTH: 13 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (12)..(12) <223> OTHERINFORMATION: Xaa is D-Pro <400> SEQUENCE: 62 Arg Leu Phe Leu Arg Arg ArgLeu Phe Arg Phe Xaa Pro 1 5 10 <210> SEQ ID NO 63 <211> LENGTH: 13 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Description of Artificial Sequence: Cyclic peptide <220>FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (12)..(12) <223>OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 63 Phe Leu Phe Leu ArgArg Arg Leu Phe Arg Arg Xaa Pro 1 5 10 <210> SEQ ID NO 64 <211> LENGTH:13 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Cyclicpeptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:(12)..(12) <223> OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 64 TyrLeu Tyr Leu Arg Arg Arg Leu Tyr Arg Arg Xaa Pro 1 5 10 <210> SEQ ID NO65 <211> LENGTH: 13 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Description of ArtificialSequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE<222> LOCATION: (12)..(12) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 65 Arg Arg Phe Leu Arg Gly Arg Phe Phe Leu Arg Xaa Pro 1 5 10<210> SEQ ID NO 66 <211> LENGTH: 13 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Descriptionof Artificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (12)..(12) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 66 Leu Leu Tyr Tyr Arg Arg Leu Tyr Tyr Arg Arg XaaPro 1 5 10 <210> SEQ ID NO 67 <211> LENGTH: 13 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (12)..(12) <223> OTHERINFORMATION: Xaa is D-Pro <400> SEQUENCE: 67 Leu Tyr Leu Tyr Arg Arg TyrLeu Tyr Arg Arg Xaa Pro 1 5 10 <210> SEQ ID NO 68 <211> LENGTH: 13 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Description of Artificial Sequence: Cyclic peptide <220>FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (12)..(12) <223>OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 68 Arg Arg Phe Phe ArgArg Leu Phe Phe Leu Leu Xaa Pro 1 5 10 <210> SEQ ID NO 69 <211> LENGTH:13 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Cyclicpeptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:(12)..(12) <223> OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 69 ArgLeu Tyr Tyr Arg Arg Leu Tyr Tyr Arg Leu Xaa Pro 1 5 10 <210> SEQ ID NO70 <211> LENGTH: 13 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Description of ArtificialSequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE<222> LOCATION: (12)..(12) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 70 Arg Leu Phe Phe Arg Gly Arg Phe Phe Arg Leu Xaa Pro 1 5 10<210> SEQ ID NO 71 <211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Descriptionof Artificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (15)..(15) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 71 Arg Tyr Leu Leu Tyr Arg Arg Arg Tyr Leu Leu TyrArg Arg Xaa Pro 1 5 10 15 <210> SEQ ID NO 72 <211> LENGTH: 16 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Description of Artificial Sequence: Cyclic peptide <220>FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (15)..(15) <223>OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 72 Arg Leu Leu Tyr TyrArg Arg Arg Tyr Leu Leu Tyr Arg Arg Xaa Pro 1 5 10 15 <210> SEQ ID NO 73<211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Description of ArtificialSequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE<222> LOCATION: (15)..(15) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 73 Arg Leu Leu Leu Tyr Arg Arg Arg Tyr Leu Tyr Tyr Arg Arg XaaPro 1 5 10 15 <210> SEQ ID NO 74 <211> LENGTH: 16 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (15)..(15) <223> OTHERINFORMATION: Xaa is D-Pro <400> SEQUENCE: 74 Arg Phe Leu Phe Leu Arg ArgArg Phe Phe Leu Phe Arg Arg Xaa Pro 1 5 10 15 <210> SEQ ID NO 75 <211>LENGTH: 16 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:Cyclic peptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>LOCATION: (15)..(15) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 75 Arg Tyr Leu Tyr Leu Arg Arg Arg Tyr Tyr Leu Tyr Arg Arg XaaPro 1 5 10 15 <210> SEQ ID NO 76 <211> LENGTH: 16 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (15)..(15) <223> OTHERINFORMATION: Xaa is D-Pro <400> SEQUENCE: 76 Arg Phe Leu Phe Leu Arg ArgArg Phe Leu Phe Leu Arg Arg Xaa Pro 1 5 10 15 <210> SEQ ID NO 77 <211>LENGTH: 16 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:Cyclic peptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>LOCATION: (15)..(15) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 77 Arg Tyr Leu Tyr Leu Arg Arg Arg Tyr Leu Tyr Leu Arg Arg XaaPro 1 5 10 15 <210> SEQ ID NO 78 <211> LENGTH: 16 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (15)..(15) <223> OTHERINFORMATION: Xaa is D-Pro <400> SEQUENCE: 78 Arg Arg Leu Leu Phe Arg ArgArg Phe Leu Leu Phe Phe Arg Xaa Pro 1 5 10 15 <210> SEQ ID NO 79 <211>LENGTH: 16 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:Cyclic peptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>LOCATION: (15)..(15) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 79 Arg Arg Leu Leu Tyr Arg Arg Arg Tyr Leu Leu Tyr Tyr Arg XaaPro 1 5 10 15 <210> SEQ ID NO 80 <211> LENGTH: 16 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (15)..(15) <223> OTHERINFORMATION: Xaa is D-Pro <400> SEQUENCE: 80 Arg Arg Leu Tyr Tyr Arg ArgArg Tyr Leu Leu Tyr Tyr Arg Xaa Pro 1 5 10 15 <210> SEQ ID NO 81 <211>LENGTH: 16 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:Cyclic peptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>LOCATION: (15)..(15) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 81 Arg Arg Leu Leu Tyr Arg Arg Arg Tyr Leu Tyr Tyr Leu Arg XaaPro 1 5 10 15 <210> SEQ ID NO 82 <211> LENGTH: 16 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (15)..(15) <223> OTHERINFORMATION: Xaa is D-Pro <400> SEQUENCE: 82 Arg Arg Leu Phe Leu Arg ArgArg Phe Phe Leu Phe Phe Arg Xaa Pro 1 5 10 15 <210> SEQ ID NO 83 <211>LENGTH: 16 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:Cyclic peptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>LOCATION: (15)..(15) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 83 Arg Arg Leu Tyr Leu Arg Arg Arg Tyr Tyr Leu Tyr Tyr Arg XaaPro 1 5 10 15 <210> SEQ ID NO 84 <211> LENGTH: 16 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (15)..(15) <223> OTHERINFORMATION: Xaa is D-Pro <400> SEQUENCE: 84 Arg Arg Leu Tyr Leu Arg ArgArg Tyr Leu Tyr Leu Tyr Arg Xaa Pro 1 5 10 15 <210> SEQ ID NO 85 <211>LENGTH: 18 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:Cyclic peptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>LOCATION: (17)..(17) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 85 Lys Arg Leu Lys Tyr Val Arg Arg Arg Trp Leu Val Lys Val LeuArg 1 5 10 15 Xaa Pro <210> SEQ ID NO 86 <211> LENGTH: 18 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Description of Artificial Sequence: Cyclic peptide <220>FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (17)..(17) <223>OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 86 Lys Arg Leu Lys TyrVal Arg Arg Gly Trp Leu Val Lys Val Leu Arg 1 5 10 15 Xaa Pro <210> SEQID NO 87 <211> LENGTH: 18 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <223> OTHER INFORMATION: Description ofArtificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (17)..(17) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 87 Lys Arg Leu Lys Tyr Trp Arg Arg Arg Trp Tyr ValLys Val Leu Arg 1 5 10 15 Xaa Pro <210> SEQ ID NO 88 <211> LENGTH: 18<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: Description of Artificial Sequence: Cyclic peptide<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (17)..(17)<223> OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 88 Lys Arg Leu TyrTyr Trp Arg Arg Arg Trp Tyr Val Phe Val Leu Arg 1 5 10 15 Xaa Pro <210>SEQ ID NO 89 <211> LENGTH: 18 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <223> OTHER INFORMATION: Description ofArtificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (17)..(17) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 89 Lys Arg Leu Lys Tyr Trp Arg Arg Gly Trp Tyr ValLys Val Leu Arg 1 5 10 15 Xaa Pro <210> SEQ ID NO 90 <211> LENGTH: 18<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: Description of Artificial Sequence: Cyclic peptide<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (17)..(17)<223> OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 90 Lys Arg Leu TyrTyr Trp Arg Arg Gly Trp Tyr Val Phe Val Leu Arg 1 5 10 15 Xaa Pro <210>SEQ ID NO 91 <211> LENGTH: 18 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <223> OTHER INFORMATION: Description ofArtificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (17)..(17) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 91 Lys Arg Leu Tyr Tyr Trp Arg Arg Arg Trp Lys ValPhe Val Leu Arg 1 5 10 15 Xaa Pro <210> SEQ ID NO 92 <211> LENGTH: 18<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: Description of Artificial Sequence: Cyclic peptide<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (17)..(17)<223> OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 92 Lys Arg Leu LysTyr Trp Arg Arg Gly Trp Lys Val Lys Val Leu Arg 1 5 10 15 Xaa Pro <210>SEQ ID NO 93 <211> LENGTH: 18 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <223> OTHER INFORMATION: Description ofArtificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (17)..(17) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 93 Tyr Lys Leu Arg Leu Lys Tyr Arg Arg Trp Lys TyrArg Val Lys Phe 1 5 10 15 Xaa Pro <210> SEQ ID NO 94 <211> LENGTH: 18<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: Description of Artificial Sequence: Cyclic peptide<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (17)..(17)<223> OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 94 Tyr Lys Leu GlnLeu Lys Trp Arg Arg Phe Lys Tyr Gln Val Lys Phe 1 5 10 15 Xaa Pro <210>SEQ ID NO 95 <211> LENGTH: 18 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <223> OTHER INFORMATION: Description ofArtificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (17)..(17) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 95 Tyr Lys Leu Gln Leu Gln Lys Lys Gly Trp Gln TyrGln Val Lys Phe 1 5 10 15 Xaa Pro <210> SEQ ID NO 96 <211> LENGTH: 14<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: Description of Artificial Sequence: Cyclic peptide<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13)<223> OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 96 Leu Arg Leu ValTyr Lys Gly Phe Leu Tyr Arg Val Xaa Pro 1 5 10 <210> SEQ ID NO 97 <211>LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:Cyclic peptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 97 Leu Arg Phe Val Tyr Lys Gly Phe Leu Tyr Arg Val Xaa Pro 1 510 <210> SEQ ID NO 98 <211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Descriptionof Artificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 98 Leu Arg Thr Val Tyr Lys Gly Phe Leu Tyr Arg ValXaa Pro 1 5 10 <210> SEQ ID NO 99 <211> LENGTH: 14 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHERINFORMATION: Xaa is D-Pro <400> SEQUENCE: 99 Leu Arg Lys Val Arg Lys GlyArg Leu Tyr Arg Val Xaa Pro 1 5 10 <210> SEQ ID NO 100 <211> LENGTH: 14<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: Description of Artificial Sequence: Cyclic peptide<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13)<223> OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 100 Leu Arg LysTrp Tyr Lys Gly Phe Trp Tyr Arg Val Xaa Pro 1 5 10 <210> SEQ ID NO 101<211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Description of ArtificialSequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE<222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 101 Leu Arg Lys Val Tyr Arg Gly Phe Leu Tyr Arg Val Xaa Pro 15 10 <210> SEQ ID NO 102 <211> LENGTH: 14 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHERINFORMATION: Xaa is D-Pro <400> SEQUENCE: 102 Leu Lys Lys Val Tyr ArgArg Phe Leu Lys Lys Val Xaa Pro 1 5 10 <210> SEQ ID NO 103 <211> LENGTH:14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Cyclicpeptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:(13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 103 LeuArg Leu Lys Tyr Arg Arg Phe Lys Tyr Arg Val Xaa Pro 1 5 10 <210> SEQ IDNO 104 <211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <223> OTHER INFORMATION: Description ofArtificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 104 Leu Arg Leu Glu Tyr Arg Arg Phe Glu Tyr ArgVal Xaa Pro 1 5 10 <210> SEQ ID NO 105 <211> LENGTH: 14 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Description of Artificial Sequence: Cyclic peptide <220>FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223>OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 105 Leu Arg Leu Gln TyrThr Thr Phe Gln Tyr Arg Val Xaa Pro 1 5 10 <210> SEQ ID NO 106 <211>LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:Cyclic peptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 106 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Pro 15 10 <210> SEQ ID NO 107 <211> LENGTH: 14 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHERINFORMATION: Xaa is D-Pro <400> SEQUENCE: 107 Leu Arg Leu Lys Trp ArgArg Lys Lys Tyr Arg Val Xaa Pro 1 5 10 <210> SEQ ID NO 108 <211> LENGTH:14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Cyclicpeptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:(13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 108 LeuArg Trp Lys Tyr Arg Arg Phe Lys Tyr Arg Val Xaa Pro 1 5 10 <210> SEQ IDNO 109 <211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <223> OTHER INFORMATION: Description ofArtificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 109 Lys Val Arg Phe Arg Arg Arg Lys Leu Lys LeuArg Xaa Pro 1 5 10 <210> SEQ ID NO 110 <211> LENGTH: 14 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Description of Artificial Sequence: Cyclic peptide <220>FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223>OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 110 Leu Arg Leu Gln TyrArg Arg Trp Gln Tyr Arg Val Xaa Pro 1 5 10 <210> SEQ ID NO 111 <211>LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:Cyclic peptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 111 Leu Arg Leu Gln Trp Arg Arg Phe Gln Tyr Arg Val Xaa Pro 15 10 <210> SEQ ID NO 112 <211> LENGTH: 14 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHERINFORMATION: Xaa is D-Pro <400> SEQUENCE: 112 Leu Arg Leu Gln Lys ArgArg Trp Gln Tyr Arg Val Xaa Pro 1 5 10 <210> SEQ ID NO 113 <211> LENGTH:14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Cyclicpeptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:(13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 113 LeuArg Leu Gln Trp Arg Arg Lys Gln Tyr Arg Val Xaa Pro 1 5 10 <210> SEQ IDNO 114 <211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <223> OTHER INFORMATION: Description ofArtificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 114 Phe Arg Leu Gln Tyr Arg Arg Phe Gln Tyr ArgVal Xaa Pro 1 5 10 <210> SEQ ID NO 115 <211> LENGTH: 14 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Description of Artificial Sequence: Cyclic peptide <220>FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223>OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 115 Leu Arg Leu Gln TyrArg Arg Phe Gln Tyr Arg Phe Xaa Pro 1 5 10 <210> SEQ ID NO 116 <211>LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:Cyclic peptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 116 Phe Arg Leu Gln Tyr Arg Arg Phe Gln Tyr Arg Phe Xaa Pro 15 10 <210> SEQ ID NO 117 <211> LENGTH: 14 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHERINFORMATION: Xaa is D-Pro <400> SEQUENCE: 117 Leu Arg Leu Gln Tyr ArgArg Phe Gln Trp Arg Val Xaa Pro 1 5 10 <210> SEQ ID NO 118 <211> LENGTH:14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Cyclicpeptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:(13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 118 LeuArg Trp Gln Tyr Arg Arg Phe Gln Tyr Arg Val Xaa Pro 1 5 10 <210> SEQ IDNO 119 <211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <223> OTHER INFORMATION: Description ofArtificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 119 Gln Val Arg Phe Arg Arg Arg Lys Leu Gln LeuArg Xaa Pro 1 5 10 <210> SEQ ID NO 120 <211> LENGTH: 14 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Description of Artificial Sequence: Cyclic peptide <220>FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223>OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 120 Phe Arg Leu Lys LysArg Arg Trp Lys Tyr Arg Val Xaa Pro 1 5 10 <210> SEQ ID NO 121 <211>LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:Cyclic peptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>LOCATION: (1)..(1) <223> OTHER INFORMATION: Xaa is Cha(L-cyclohexylalanine) <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 121 Xaa Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Pro 15 10 <210> SEQ ID NO 122 <211> LENGTH: 14 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (1)..(1) <223> OTHER INFORMATION:Xaa is hPhe (L-homo-phenylalanine) <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 122 Xaa Arg Leu Lys Lys Arg Arg Trp Lys Tyr ArgVal Xaa Pro 1 5 10 <210> SEQ ID NO 123 <211> LENGTH: 14 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Description of Artificial Sequence: Cyclic peptide <220>FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (1)..(1) <223>OTHER INFORMATION: Xaa is 2-Nal (L-2-naphthylalanine) <220> FEATURE:<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHERINFORMATION: Xaa is D-Pro <400> SEQUENCE: 123 Xaa Arg Leu Lys Lys ArgArg Trp Lys Tyr Arg Val Xaa Pro 1 5 10 <210> SEQ ID NO 124 <211> LENGTH:14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Cyclicpeptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:(1)..(1) <223> OTHER INFORMATION: Xaa is 1-Nal (L-1-naphthylalanine)<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13)<223> OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 124 Xaa Arg LeuLys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Pro 1 5 10 <210> SEQ ID NO 125<211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Description of ArtificialSequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE<222> LOCATION: (1)..(1) <223> OTHER INFORMATION: Xaa is Nle(L-norleucine) <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 125 Xaa Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Pro 15 10 <210> SEQ ID NO 126 <211> LENGTH: 14 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHERINFORMATION: Xaa is D-Pro <400> SEQUENCE: 126 Leu Arg Phe Lys Lys ArgArg Trp Lys Tyr Arg Val Xaa Pro 1 5 10 <210> SEQ ID NO 127 <211> LENGTH:14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Cyclicpeptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:(3)..(3) <223> OTHER INFORMATION: Xaa is Cha (L-cyclohexylalanine) <220>FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223>OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 127 Leu Arg Xaa Lys LysArg Arg Trp Lys Tyr Arg Val Xaa Pro 1 5 10 <210> SEQ ID NO 128 <211>LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:Cyclic peptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>LOCATION: (3)..(3) <223> OTHER INFORMATION: Xaa is Y(Bzl)[L-O-benzyltyrosine] <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 128 Leu Arg Xaa Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Pro 15 10 <210> SEQ ID NO 129 <211> LENGTH: 14 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHERINFORMATION: Xaa is D-Pro <400> SEQUENCE: 129 Leu Arg Trp Lys Lys ArgArg Trp Lys Tyr Arg Val Xaa Pro 1 5 10 <210> SEQ ID NO 130 <211> LENGTH:14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Cyclicpeptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:(3)..(3) <223> OTHER INFORMATION: Xaa is hPhe (L-homo-phenylalanine)<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13)<223> OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 130 Leu Arg XaaLys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Pro 1 5 10 <210> SEQ ID NO 131<211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Description of ArtificialSequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE<222> LOCATION: (3)..(3) <223> OTHER INFORMATION: Xaa is 2-Nal(L-2-naphthylalanine) <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 131 Leu Arg Xaa Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Pro 15 10 <210> SEQ ID NO 132 <211> LENGTH: 14 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (3)..(3) <223> OTHER INFORMATION:Xaa is 1-Nal (L-1-naphthylalanine) <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 132 Leu Arg Xaa Lys Lys Arg Arg Trp Lys Tyr ArgVal Xaa Pro 1 5 10 <210> SEQ ID NO 133 <211> LENGTH: 14 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Description of Artificial Sequence: Cyclic peptide <220>FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223>OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 133 Leu Arg Val Lys LysArg Arg Trp Lys Tyr Arg Val Xaa Pro 1 5 10 <210> SEQ ID NO 134 <211>LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:Cyclic peptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 134 Leu Arg Ile Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Pro 15 10 <210> SEQ ID NO 135 <211> LENGTH: 14 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (3)..(3) <223> OTHER INFORMATION:Xaa is Nle (L-norleucine) <220> FEATURE: <221> NAME/KEY: MISC_FEATURE<222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 135 Leu Arg Xaa Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Pro 15 10 <210> SEQ ID NO 136 <211> LENGTH: 14 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHERINFORMATION: Xaa is D-Pro <400> SEQUENCE: 136 Leu Arg Leu Lys Lys ArgArg Tyr Lys Tyr Arg Val Xaa Pro 1 5 10 <210> SEQ ID NO 137 <211> LENGTH:14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Cyclicpeptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:(8)..(8) <223> OTHER INFORMATION: Xaa is Y(Bzl) [L-O-benzyltyrosine]<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13)<223> OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 137 Leu Arg LeuLys Lys Arg Arg Xaa Lys Tyr Arg Val Xaa Pro 1 5 10 <210> SEQ ID NO 138<211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Description of ArtificialSequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE<222> LOCATION: (8)..(8) <223> OTHER INFORMATION: Xaa is hPhe(L-homo-phenylalanine) <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 138 Leu Arg Leu Lys Lys Arg Arg Xaa Lys Tyr Arg Val Xaa Pro 15 10 <210> SEQ ID NO 139 <211> LENGTH: 14 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (8)..(8) <223> OTHER INFORMATION:Xaa is 2-Nal (L-2-naphthylalanine) <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 139 Leu Arg Leu Lys Lys Arg Arg Xaa Lys Tyr ArgVal Xaa Pro 1 5 10 <210> SEQ ID NO 140 <211> LENGTH: 14 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Description of Artificial Sequence: Cyclic peptide <220>FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (8)..(8) <223>OTHER INFORMATION: Xaa is 1-Nal (L-1-naphthylalanine) <220> FEATURE:<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHERINFORMATION: Xaa is D-Pro <400> SEQUENCE: 140 Leu Arg Leu Lys Lys ArgArg Xaa Lys Tyr Arg Val Xaa Pro 1 5 10 <210> SEQ ID NO 141 <211> LENGTH:14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Cyclicpeptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:(13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 141 LeuArg Leu Lys Lys Arg Arg Val Lys Tyr Arg Cys Xaa Pro 1 5 10 <210> SEQ IDNO 142 <211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <223> OTHER INFORMATION: Description ofArtificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 142 Leu Arg Leu Lys Lys Arg Arg Ile Lys Tyr ArgVal Xaa Pro 1 5 10 <210> SEQ ID NO 143 <211> LENGTH: 14 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Description of Artificial Sequence: Cyclic peptide <220>FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223>OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 143 Leu Arg Leu Lys LysArg Arg Leu Lys Tyr Arg Val Xaa Pro 1 5 10 <210> SEQ ID NO 144 <211>LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:Cyclic peptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>LOCATION: (8)..(8) <223> OTHER INFORMATION: Xaa is Nle (L-norleucine)<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13)<223> OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 144 Leu Arg LeuLys Lys Arg Arg Xaa Lys Tyr Arg Val Xaa Pro 1 5 10 <210> SEQ ID NO 145<211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Description of ArtificialSequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE<222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 145 Leu Arg Leu Lys Lys Arg Arg His Lys Tyr Arg Val Xaa Pro 15 10 <210> SEQ ID NO 146 <211> LENGTH: 14 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHERINFORMATION: Xaa is D-Pro <400> SEQUENCE: 146 Leu Arg Leu Lys Lys ArgArg Trp Lys Phe Arg Val Xaa Pro 1 5 10 <210> SEQ ID NO 147 <211> LENGTH:14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Cyclicpeptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:(10)..(10) <223> OTHER INFORMATION: Xaa is Y(Bzl) [L-O-benzyltyrosine]<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13)<223> OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 147 Leu Arg LeuLys Lys Arg Arg Trp Lys Xaa Arg Val Xaa Pro 1 5 10 <210> SEQ ID NO 148<211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Description of ArtificialSequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE<222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 148 Leu Arg Leu Lys Lys Arg Arg Trp Lys Trp Arg Val Xaa Pro 15 10 <210> SEQ ID NO 149 <211> LENGTH: 14 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (10)..(10) <223> OTHERINFORMATION: Xaa is hPhe (L-homo-phenylalanine) <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHERINFORMATION: Xaa is D-Pro <400> SEQUENCE: 149 Leu Arg Leu Lys Lys ArgArg Trp Lys Xaa Arg Val Xaa Pro 1 5 10 <210> SEQ ID NO 150 <211> LENGTH:14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Cyclicpeptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:(10)..(10) <223> OTHER INFORMATION: Xaa is 1-Nal (L-1-naphthylalanine)<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13)<223> OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 150 Leu Arg LeuLys Lys Arg Arg Trp Lys Xaa Arg Val Xaa Pro 1 5 10 <210> SEQ ID NO 151<211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Description of ArtificialSequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE<222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 151 Leu Arg Leu Lys Lys Arg Arg Trp Lys Val Arg Val Xaa Pro 15 10 <210> SEQ ID NO 152 <211> LENGTH: 14 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHERINFORMATION: Xaa is D-Pro <400> SEQUENCE: 152 Leu Arg Leu Lys Lys ArgArg Trp Lys Ile Arg Val Xaa Pro 1 5 10 <210> SEQ ID NO 153 <211> LENGTH:14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Cyclicpeptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:(13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 153 LeuArg Leu Lys Lys Arg Arg Trp Lys Leu Arg Val Xaa Pro 1 5 10 <210> SEQ IDNO 154 <211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <223> OTHER INFORMATION: Description ofArtificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (10)..(10) <223> OTHER INFORMATION: Xaa isNle (L-norleucine) <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 154 Leu Arg Leu Lys Lys Arg Arg Trp Lys Xaa Arg Val Xaa Pro 15 10 <210> SEQ ID NO 155 <211> LENGTH: 14 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHERINFORMATION: Xaa is D-Pro <400> SEQUENCE: 155 Leu Arg Leu Lys Lys ArgArg Trp Lys Tyr Arg Phe Xaa Pro 1 5 10 <210> SEQ ID NO 156 <211> LENGTH:14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Cyclicpeptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:(12)..(12) <223> OTHER INFORMATION: Xaa is Cha (L-cyclohexylalanine)<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13)<223> OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 156 Leu Arg LeuLys Lys Arg Arg Trp Lys Tyr Arg Xaa Xaa Pro 1 5 10 <210> SEQ ID NO 157<211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Description of ArtificialSequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE<222> LOCATION: (12)..(12) <223> OTHER INFORMATION: Xaa is Y (Bzl)[L-O-benzyltyrosine] <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 157 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Xaa Xaa Pro 15 10 <210> SEQ ID NO 158 <211> LENGTH: 14 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHERINFORMATION: Xaa is D-Pro <400> SEQUENCE: 158 Leu Arg Leu Lys Lys ArgArg Trp Lys Tyr Arg Trp Xaa Pro 1 5 10 <210> SEQ ID NO 159 <211> LENGTH:14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Cyclicpeptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:(12)..(12) <223> OTHER INFORMATION: Xaa is hPhe (L-homo-phenylalanine)<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13)<223> OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 159 Leu Arg LeuLys Lys Arg Arg Trp Lys Tyr Arg Xaa Xaa Pro 1 5 10 <210> SEQ ID NO 160<211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Description of ArtificialSequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE<222> LOCATION: (12)..(12) <223> OTHER INFORMATION: Xaa is 2-Nal(L-2-naphthylalanine) <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 160 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Xaa Xaa Pro 15 10 <210> SEQ ID NO 161 <211> LENGTH: 14 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (12)..(12) <223> OTHERINFORMATION: Xaa is 1-Nal (L-1-naphthylalanine) <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHERINFORMATION: Xaa is D-Pro <400> SEQUENCE: 161 Leu Arg Leu Lys Lys ArgArg Trp Lys Tyr Arg Xaa Xaa Pro 1 5 10 <210> SEQ ID NO 162 <211> LENGTH:14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Cyclicpeptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:(13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 162 LeuArg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Ile Xaa Pro 1 5 10 <210> SEQ IDNO 163 <211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <223> OTHER INFORMATION: Description ofArtificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (12)..(12) <223> OTHER INFORMATION: Xaa isNle (L-norleucine) <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 163 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Xaa Xaa Pro 15 10 <210> SEQ ID NO 164 <211> LENGTH: 14 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHERINFORMATION: Xaa is D-Pro <400> SEQUENCE: 164 Leu Arg Leu Lys Lys ArgArg Trp Lys Tyr Arg His Xaa Pro 1 5 10 <210> SEQ ID NO 165 <211> LENGTH:14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Cyclicpeptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:(13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 165 LeuTrp Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Pro 1 5 10 <210> SEQ IDNO 166 <211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <223> OTHER INFORMATION: Description ofArtificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 166 Leu Leu Leu Lys Lys Arg Arg Trp Lys Tyr ArgVal Xaa Pro 1 5 10 <210> SEQ ID NO 167 <211> LENGTH: 14 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Description of Artificial Sequence: Cyclic peptide <220>FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223>OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 167 Leu Thr Leu Lys LysArg Arg Trp Lys Tyr Arg Val Xaa Pro 1 5 10 <210> SEQ ID NO 168 <211>LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:Cyclic peptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 168 Leu Gln Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Pro 15 10 <210> SEQ ID NO 169 <211> LENGTH: 14 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHERINFORMATION: Xaa is D-Pro <400> SEQUENCE: 169 Leu Arg Leu Leu Lys ArgArg Trp Lys Tyr Arg Val Xaa Pro 1 5 10 <210> SEQ ID NO 170 <211> LENGTH:14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Cyclicpeptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:(13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 170 LeuArg Leu Arg Lys Arg Arg Trp Lys Tyr Arg Val Xaa Pro 1 5 10 <210> SEQ IDNO 171 <211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <223> OTHER INFORMATION: Description ofArtificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 171 Leu Arg Leu Thr Lys Arg Arg Trp Lys Tyr ArgVal Xaa Pro 1 5 10 <210> SEQ ID NO 172 <211> LENGTH: 14 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Description of Artificial Sequence: Cyclic peptide <220>FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223>OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 172 Leu Arg Leu Gln LysArg Arg Trp Lys Tyr Arg Val Xaa Pro 1 5 10 <210> SEQ ID NO 173 <211>LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:Cyclic peptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 173 Leu Arg Leu Lys Leu Arg Arg Trp Lys Tyr Arg Val Xaa Pro 15 10 <210> SEQ ID NO 174 <211> LENGTH: 14 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHERINFORMATION: Xaa is D-Pro <400> SEQUENCE: 174 Leu Arg Leu Lys His ArgArg Trp Lys Tyr Arg Val Xaa Pro 1 5 10 <210> SEQ ID NO 175 <211> LENGTH:14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Cyclicpeptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:(13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 175 LeuArg Leu Lys Arg Arg Arg Trp Lys Tyr Arg Val Xaa Pro 1 5 10 <210> SEQ IDNO 176 <211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <223> OTHER INFORMATION: Description ofArtificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 176 Leu Arg Leu Lys Thr Arg Arg Trp Lys Tyr ArgVal Xaa Pro 1 5 10 <210> SEQ ID NO 177 <211> LENGTH: 14 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Description of Artificial Sequence: Cyclic peptide <220>FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223>OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 177 Leu Arg Leu Lys LysLeu Arg Trp Lys Tyr Arg Val Xaa Pro 1 5 10 <210> SEQ ID NO 178 <211>LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:Cyclic peptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 178 Leu Arg Leu Lys Lys His Arg Trp Lys Tyr Arg Val Xaa Pro 15 10 <210> SEQ ID NO 179 <211> LENGTH: 14 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHERINFORMATION: Xaa is D-Pro <400> SEQUENCE: 179 Leu Arg Leu Lys Lys LysArg Trp Lys Tyr Arg Val Xaa Pro 1 5 10 <210> SEQ ID NO 180 <211> LENGTH:14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Cyclicpeptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:(13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 180 LeuArg Leu Lys Lys Thr Arg Trp Lys Tyr Arg Val Xaa Pro 1 5 10 <210> SEQ IDNO 181 <211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <223> OTHER INFORMATION: Description ofArtificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 181 Leu Arg Leu Lys Lys Gln Arg Trp Lys Tyr ArgVal Xaa Pro 1 5 10 <210> SEQ ID NO 182 <211> LENGTH: 14 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Description of Artificial Sequence: Cyclic peptide <220>FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223>OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 182 Leu Arg Leu Lys LysArg Trp Trp Lys Tyr Arg Val Xaa Pro 1 5 10 <210> SEQ ID NO 183 <211>LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:Cyclic peptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 183 Leu Arg Leu Lys Lys Arg His Trp Lys Tyr Arg Val Xaa Pro 15 10 <210> SEQ ID NO 184 <211> LENGTH: 14 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHERINFORMATION: Xaa is D-Pro <400> SEQUENCE: 184 Leu Arg Leu Lys Lys ArgLys Trp Lys Tyr Arg Val Xaa Pro 1 5 10 <210> SEQ ID NO 185 <211> LENGTH:14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Cyclicpeptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:(1)..(1) <223> OTHER INFORMATION: Xaa is Bip [L-(4-phenyl)phenylalanine]<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13)<223> OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 185 Xaa Arg LeuLys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Pro 1 5 10 <210> SEQ ID NO 186<211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Description of ArtificialSequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE<222> LOCATION: (1)..(1) <223> OTHER INFORMATION: Xaa is 4Cl-Phe(L-4-chlorophenylalanine) <220> FEATURE: <221> NAME/KEY: MISC_FEATURE<222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 186 Xaa Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Pro 15 10 <210> SEQ ID NO 187 <211> LENGTH: 14 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (1)..(1) <223> OTHER INFORMATION:Xaa is AmPhe (L-aminophenylalanine) <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 187 Xaa Arg Leu Lys Lys Arg Arg Trp Lys Tyr ArgVal Xaa Pro 1 5 10 <210> SEQ ID NO 188 <211> LENGTH: 14 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Description of Artificial Sequence: Cyclic peptide <220>FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (1)..(1) <223>OTHER INFORMATION: Xaa is S(Bzl) [L-O-benzylserine] <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHERINFORMATION: Xaa is D-Pro <400> SEQUENCE: 188 Xaa Arg Leu Lys Lys ArgArg Trp Lys Tyr Arg Val Xaa Pro 1 5 10 <210> SEQ ID NO 189 <211> LENGTH:14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Cyclicpeptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:(1)..(1) <223> OTHER INFORMATION: Xaa is T(Bzl) [L-O-benzylthreonine)<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13)<223> OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 189 Xaa Arg LeuLys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Pro 1 5 10 <210> SEQ ID NO 190<211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Description of ArtificialSequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE<222> LOCATION: (1)..(1) <223> OTHER INFORMATION: Xaa is Orn(L-ornithine) <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 190 Xaa Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Pro 15 10 <210> SEQ ID NO 191 <211> LENGTH: 14 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (3)..(3) <223> OTHER INFORMATION:Xaa is Bip [L-(4-phenyl)phenylalanine] <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 191 Leu Arg Xaa Lys Lys Arg Arg Trp Lys Tyr ArgVal Xaa Pro 1 5 10 <210> SEQ ID NO 192 <211> LENGTH: 14 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Description of Artificial Sequence: Cyclic peptide <220>FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (3)..(3) <223>OTHER INFORMATION: Xaa is 4Cl-Phe (L-4-chlorophenylalanine) <220>FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223>OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 192 Leu Arg Xaa Lys LysArg Arg Trp Lys Tyr Arg Val Xaa Pro 1 5 10 <210> SEQ ID NO 193 <211>LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:Cyclic peptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>LOCATION: (3)..(3) <223> OTHER INFORMATION: Xaa is AmPhe(aminophenylalanine) <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 193 Leu Arg Xaa Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Pro 15 10 <210> SEQ ID NO 194 <211> LENGTH: 14 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (3)..(3) <223> OTHER INFORMATION:Xaa is S(Bzl) [L-O-benzyltyrosine] <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 194 Leu Arg Xaa Lys Lys Arg Arg Trp Lys Tyr ArgVal Xaa Pro 1 5 10 <210> SEQ ID NO 195 <211> LENGTH: 14 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Description of Artificial Sequence: Cyclic peptide <220>FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (3)..(3) <223>OTHER INFORMATION: Xaa is T(Bzl) [L-O-benzylthreonine] <220> FEATURE:<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHERINFORMATION: Xaa is D-Pro <400> SEQUENCE: 195 Leu Arg Xaa Lys Lys ArgArg Trp Lys Tyr Arg Val Xaa Pro 1 5 10 <210> SEQ ID NO 196 <211> LENGTH:14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Cyclicpeptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:(3)..(3) <223> OTHER INFORMATION: Xaa is Orn (L-ornithine) <220>FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223>OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 196 Leu Arg Xaa Lys LysArg Trp Trp Lys Tyr Arg Val Xaa Pro 1 5 10 <210> SEQ ID NO 197 <211>LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:Cyclic peptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>LOCATION: (8)..(8) <223> OTHER INFORMATION: Xaa is Bip[L-(4-phenyl)phenylalanine] <220> FEATURE: <221> NAME/KEY: MISC_FEATURE<222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 197 Leu Arg Leu Lys Lys Arg Arg Xaa Lys Tyr Arg Val Xaa Pro 15 10 <210> SEQ ID NO 198 <211> LENGTH: 14 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (8)..(8) <223> OTHER INFORMATION:Xaa is 4Cl-Phe (L-4-chlorophenylalanine) <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 198 Leu Arg Leu Lys Lys Arg Arg Xaa Lys Tyr ArgVal Xaa Pro 1 5 10 <210> SEQ ID NO 199 <211> LENGTH: 14 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Description of Artificial Sequence: Cyclic peptide <220>FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (8)..(8) <223>OTHER INFORMATION: Xaa is AmPhe (L-aminophenylalanine) <220> FEATURE:<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHERINFORMATION: Xaa is D-Pro <400> SEQUENCE: 199 Leu Arg Leu Leu Lys ArgArg Xaa Lys Tyr Arg Val Xaa Pro 1 5 10 <210> SEQ ID NO 200 <211> LENGTH:14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Cyclicpeptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:(8)..(8) <223> OTHER INFORMATION: Xaa is S(Bzl) [L-O-benzylserine] <220>FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223>OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 200 Leu Arg Leu Lys LysArg Arg Xaa Lys Tyr Arg Val Xaa Pro 1 5 10 <210> SEQ ID NO 201 <211>LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:Cyclic peptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>LOCATION: (8)..(8) <223> OTHER INFORMATION: Xaa is T(Bzl)[L-O-benzylthreonine] <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 201 Leu Arg Leu Lys Lys Arg Arg Xaa Lys Tyr Arg Val Xaa Pro 15 10 <210> SEQ ID NO 202 <211> LENGTH: 14 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (8)..(8) <223> OTHER INFORMATION:Xaa in position 8 is Orn (L-Ornithine) <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 202 Leu Arg Leu Lys Lys Arg Arg Xaa Lys Tyr ArgVal Xaa Pro 1 5 10 <210> SEQ ID NO 203 <211> LENGTH: 14 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Description of Artificial Sequence: Cyclic peptide <220>FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (10)..(10) <223>OTHER INFORMATION: Xaa is Bip [L-(4-phenyl)phenylalanine] <220> FEATURE:<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHERINFORMATION: Xaa is D-Pro <400> SEQUENCE: 203 Leu Arg Leu Lys Lys ArgArg Trp Lys Xaa Arg Val Xaa Pro 1 5 10 <210> SEQ ID NO 204 <211> LENGTH:14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Cyclicpeptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:(10)..(10) <223> OTHER INFORMATION: Xaa is 4Cl-Phe(L-4-chlorophenylalanine) <220> FEATURE: <221> NAME/KEY: MISC_FEATURE<222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 204 Leu Arg Leu Lys Lys Arg Arg Trp Lys Xaa Arg Val Xaa Pro 15 10 <210> SEQ ID NO 205 <211> LENGTH: 14 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (10)..(10) <223> OTHERINFORMATION: Xaa is S(Bzl) [L-O-benzylserine] <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHERINFORMATION: Xaa is D-Pro <400> SEQUENCE: 205 Leu Arg Leu Lys Lys ArgArg Trp Lys Xaa Arg Val Xaa Pro 1 5 10 <210> SEQ ID NO 206 <211> LENGTH:14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Cyclicpeptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:(10)..(10) <223> OTHER INFORMATION: Xaa is T(Bzl) [L-O-benzylthreonine]<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13)<223> OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 206 Leu Arg LeuLys Lys Arg Arg Trp Lys Xaa Arg Val Xaa Pro 1 5 10 <210> SEQ ID NO 207<211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Description of ArtificialSequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE<222> LOCATION: (10)..(10) <223> OTHER INFORMATION: Xaa is Orn(L-Ornithine) <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 207 Leu Arg Leu Lys Lys Arg Arg Trp Lys Xaa Arg Val Xaa Pro 15 10 <210> SEQ ID NO 208 <211> LENGTH: 14 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (12)..(12) <223> OTHERINFORMATION: Xaa is Bip [L-(4-phenyl)phenylalanine] <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHERINFORMATION: Xaa is D-Pro <400> SEQUENCE: 208 Leu Arg Leu Lys Lys ArgArg Trp Lys Tyr Arg Xaa Xaa Pro 1 5 10 <210> SEQ ID NO 209 <211> LENGTH:14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Cyclicpeptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:(12)..(12) <223> OTHER INFORMATION: Xaa is ccl-Phe(L-4-chlorophenylalanine) <220> FEATURE: <221> NAME/KEY: MISC_FEATURE<222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 209 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Xaa Xaa Pro 15 10 <210> SEQ ID NO 210 <211> LENGTH: 14 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (12)..(12) <223> OTHERINFORMATION: Xaa is AmPhe (L-aminophenylalanine) <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHERINFORMATION: Xaa is D-Pro <400> SEQUENCE: 210 Leu Arg Leu Lys Lys ArgArg Trp Lys Tyr Arg Xaa Xaa Pro 1 5 10 <210> SEQ ID NO 211 <211> LENGTH:14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Cyclicpeptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:(12)..(12) <223> OTHER INFORMATION: Xaa is T(Bzl) [L-O-benzylthreonine]<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13)<223> OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 211 Leu Arg LeuLys Lys Arg Arg Trp Lys Tyr Arg Xaa Xaa Pro 1 5 10 <210> SEQ ID NO 212<211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Description of ArtificialSequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE<222> LOCATION: (12)..(12) <223> OTHER INFORMATION: Xaa is Orn(L-ornithine) <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 212 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Xaa Xaa Pro 15 10 <210> SEQ ID NO 213 <211> LENGTH: 14 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (2)..(2) <223> OTHER INFORMATION:Xaa is Orn (L-ornithine) <220> FEATURE: <221> NAME/KEY: MISC_FEATURE<222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 213 Leu Xaa Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Pro 15 10 <210> SEQ ID NO 214 <211> LENGTH: 14 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (4)..(4) <223> OTHER INFORMATION:Xaa is Orn (L-ornithine) <220> FEATURE: <221> NAME/KEY: MISC_FEATURE<222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 214 Leu Arg Leu Xaa Lys Arg Arg Trp Lys Tyr Arg Val Xaa Pro 15 10 <210> SEQ ID NO 215 <211> LENGTH: 14 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (5)..(5) <223> OTHER INFORMATION:Xaa is Orn (L-ornithine) <220> FEATURE: <221> NAME/KEY: MISC_FEATURE<222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 215 Leu Arg Leu Lys Xaa Arg Arg Trp Lys Tyr Arg Val Xaa Pro 15 10 <210> SEQ ID NO 216 <211> LENGTH: 14 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (7)..(7) <223> OTHER INFORMATION:Xaa is Orn (L-ornithine) <220> FEATURE: <221> NAME/KEY: MISC_FEATURE<222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 216 Leu Arg Leu Lys Lys Arg Xaa Trp Lys Tyr Arg Val Xaa Pro 15 10 <210> SEQ ID NO 217 <211> LENGTH: 14 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (9)..(9) <223> OTHER INFORMATION:Xaa is Orn (L-ornithine) <220> FEATURE: <221> NAME/KEY: MISC_FEATURE<222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 217 Leu Arg Leu Lys Lys Arg Arg Trp Xaa Tyr Arg Val Xaa Pro 15 10 <210> SEQ ID NO 218 <211> LENGTH: 14 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (11)..(11) <223> OTHERINFORMATION: Xaa is Orn (L-ornithine) <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 218 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr XaaVal Xaa Pro 1 5 10 <210> SEQ ID NO 219 <211> LENGTH: 14 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Description of Artificial Sequence: Cyclic peptide <220>FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223>OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 219 Leu Arg Leu Lys LysArg Gln Trp Lys Tyr Arg Val Xaa Pro 1 5 10 <210> SEQ ID NO 220 <211>LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:Cyclic peptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 220 Leu Arg Leu Lys Lys Arg Arg Trp Tyr Tyr Arg Val Xaa Pro 15 10 <210> SEQ ID NO 221 <211> LENGTH: 14 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHERINFORMATION: Xaa is D-Pro <400> SEQUENCE: 221 Leu Arg Leu Lys Lys ArgArg Trp His Tyr Arg Val Xaa Pro 1 5 10 <210> SEQ ID NO 222 <211> LENGTH:14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Cyclicpeptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:(13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 222 LeuArg Leu Lys Lys Arg Arg Trp Arg Tyr Arg Val Xaa Pro 1 5 10 <210> SEQ IDNO 223 <211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <223> OTHER INFORMATION: Description ofArtificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 223 Leu Arg Leu Lys Lys Arg Arg Trp Thr Tyr ArgVal Xaa Pro 1 5 10 <210> SEQ ID NO 224 <211> LENGTH: 14 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Description of Artificial Sequence: Cyclic peptide <220>FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223>OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 224 Leu Arg Leu Lys LysArg Arg Trp Gln Tyr Arg Val Xaa Pro 1 5 10 <210> SEQ ID NO 225 <211>LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:Cyclic peptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 225 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Tyr Val Xaa Pro 15 10 <210> SEQ ID NO 226 <211> LENGTH: 14 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHERINFORMATION: Xaa is D-Pro <400> SEQUENCE: 226 Leu Arg Leu Lys Lys ArgArg Trp Lys Tyr Trp Val Xaa Pro 1 5 10 <210> SEQ ID NO 227 <211> LENGTH:14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Cyclicpeptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:(8)..(8) <223> OTHER INFORMATION: Xaa is Bip [L-(4-phenyl)phenylalanine]<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (10)..(10)<223> OTHER INFORMATION: Xaa is Bip [L-(4-phenyl)phenylalanine] <220>FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223>OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 227 Leu Arg Leu Lys LysArg Arg Xaa Lys Xaa Arg Val Xaa Pro 1 5 10 <210> SEQ ID NO 228 <211>LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:Cyclic peptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>LOCATION: (8)..(8) <223> OTHER INFORMATION: Xaa is Bip[L-(4-phenyl)phenylalanine] <220> FEATURE: <221> NAME/KEY: MISC_FEATURE<222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 228 Leu Arg Leu Arg Lys Arg Arg Xaa Lys Tyr Arg Val Xaa Pro 15 10 <210> SEQ ID NO 229 <211> LENGTH: 14 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (8)..(8) <223> OTHER INFORMATION:Xaa is Bip [L-(4-phenyl)phenylalanine] <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 229 Leu Arg Leu Lys Lys Arg Arg Xaa Lys Tyr ArgVal Xaa Pro 1 5 10 <210> SEQ ID NO 230 <211> LENGTH: 14 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Description of Artificial Sequence: Cyclic peptide <220>FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (8)..(8) <223>OTHER INFORMATION: Xaa is Bip [L-(4-phenyl)phenylalanine] <220> FEATURE:<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHERINFORMATION: Xaa is D-Pro <400> SEQUENCE: 230 Leu Trp Leu Lys Lys ArgArg Xaa Lys Tyr Arg Val Xaa Pro 1 5 10 <210> SEQ ID NO 231 <211> LENGTH:14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Cyclicpeptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:(8)..(8) <223> OTHER INFORMATION: Xaa is Bip [L-(4-phenyl)phenylalanine]<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13)<223> OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 231 Leu Trp LeuArg Lys Arg Arg Xaa Lys Tyr Arg Val Xaa Pro 1 5 10 <210> SEQ ID NO 232<211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Description of ArtificialSequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE<222> LOCATION: (8)..(8) <223> OTHER INFORMATION: Xaa is Bip[L-(4-phenyl)phenylalanine] <220> FEATURE: <221> NAME/KEY: MISC_FEATURE<222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 232 Leu Trp Leu Lys Lys Arg Arg Xaa Arg Tyr Arg Val Xaa Pro 15 10 <210> SEQ ID NO 233 <211> LENGTH: 14 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (8)..(8) <223> OTHER INFORMATION:Xaa is Bip [L-(4-phenyl)phenylalanine] <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (10)..(10) <223> OTHER INFORMATION: Xaa isBip [L-(4-phenyl)phenylalanine] <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 233 Leu Trp Leu Arg Lys Arg Arg Xaa Lys Xaa ArgVal Xaa Pro 1 5 10 <210> SEQ ID NO 234 <211> LENGTH: 14 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Description of Artificial Sequence: Cyclic peptide <220>FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (8)..(8) <223>OTHER INFORMATION: Xaa is Bip [L-(4-phenyl)phenylalanine] <220> FEATURE:<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (10)..(10) <223> OTHERINFORMATION: Xaa is Bip [L-(4-phenyl)phenylalanine] <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHERINFORMATION: Xaa is D-Pro <400> SEQUENCE: 234 Leu Trp Leu Lys Lys ArgArg Xaa Arg Xaa Arg Val Xaa Pro 1 5 10 <210> SEQ ID NO 235 <211> LENGTH:14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Cyclicpeptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:(8)..(8) <223> OTHER INFORMATION: Xaa is Bip [L-(4-phenyl)phenylalanine]<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (10)..(10)<223> OTHER INFORMATION: Xaa is Bip [L-(4-phenyl)phenylalanine] <220>FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (12)..(12) <223>OTHER INFORMATION: Xaa is Bip [L-(4-phenyl)phenylalanine] <220> FEATURE:<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHERINFORMATION: Xaa is D-Pro <400> SEQUENCE: 235 Leu Trp Leu Arg Lys ArgArg Xaa Arg Xaa Arg Xaa Xaa Pro 1 5 10 <210> SEQ ID NO 236 <211> LENGTH:14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Cyclicpeptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:(1)..(1) <223> OTHER INFORMATION: Xaa is 4Cl-Phe(L-4-chlorophenylalanine) <220> FEATURE: <221> NAME/KEY: MISC_FEATURE<222> LOCATION: (8)..(8) <223> OTHER INFORMATION: Xaa is Bip[L-(4-phenyl)phenylalanine] <220> FEATURE: <221> NAME/KEY: MISC_FEATURE<222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 236 Xaa Arg Leu Lys Lys Arg Arg Xaa Lys Tyr Arg Val Xaa Pro 15 10 <210> SEQ ID NO 237 <211> LENGTH: 14 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (1)..(1) <223> OTHER INFORMATION:Xaa is 4Cl-Phe (L-4-chlorophenylalanine) <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (8)..(8) <223> OTHER INFORMATION: Xaa isBip [L-(4-phenyl)phenylalanine] <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (10)..(10) <223> OTHER INFORMATION: Xaa isBip [L-(4-phenyl)phenylalanine] <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 237 Xaa Arg Leu Lys Lys Arg Arg Xaa Lys Xaa ArgVal Xaa Pro 1 5 10 <210> SEQ ID NO 238 <211> LENGTH: 14 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Description of Artificial Sequence: Cyclic peptide <220>FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (1)..(1) <223>OTHER INFORMATION: Xaa is 4Cl-Phe (L-4-chlorophenylalanine) <220>FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (8)..(8) <223>OTHER INFORMATION: Xaa is Bip [L-(4-phenyl)phenylalanine] <220> FEATURE:<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (12)..(12) <223> OTHERINFORMATION: Xaa is Bip [L-(4-phenyl)phenylalanine] <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHERINFORMATION: Xaa is D-Pro <400> SEQUENCE: 238 Xaa Arg Leu Lys Lys ArgArg Xaa Lys Tyr Arg Xaa Xaa Pro 1 5 10 <210> SEQ ID NO 239 <211> LENGTH:14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Cyclicpeptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:(1)..(1) <223> OTHER INFORMATION: Xaa is 4Cl-Phe (4-chlorophenylalanine)<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (8)..(8)<223> OTHER INFORMATION: Xaa is Bip [L-(4-phenyl)phenylalanine] <220>FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (10)..(10) <223>OTHER INFORMATION: Xaa is Bip [L-(4-phenyl)phenylalanine] <220> FEATURE:<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (12)..(12) <223> OTHERINFORMATION: Xaa is Bip [L-(4-phenyl)phenylalanine] <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHERINFORMATION: Xaa is D-Pro <400> SEQUENCE: 239 Xaa Arg Leu Lys Lys ArgArg Xaa Lys Xaa Arg Xaa Xaa Pro 1 5 10 <210> SEQ ID NO 240 <211> LENGTH:14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Cyclicpeptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:(1)..(1) <223> OTHER INFORMATION: Xaa is 4Cl-Phe (4-chlorophenylalanine)<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (8)..(8)<223> OTHER INFORMATION: Xaa is Bip [L-(4-phenyl)phenylalanine] <220>FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223>OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 240 Xaa Arg Leu Arg LysArg Arg Xaa Lys Tyr Arg Val Xaa Pro 1 5 10 <210> SEQ ID NO 241 <211>LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:Cyclic peptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>LOCATION: (1)..(1) <223> OTHER INFORMATION: Xaa is 4Cl-Phe(4-chlorophenylalanine) <220> FEATURE: <221> NAME/KEY: MISC_FEATURE<222> LOCATION: (8)..(8) <223> OTHER INFORMATION: Xaa is Bip[L-(4-phenyl)phenylalanine] <220> FEATURE: <221> NAME/KEY: MISC_FEATURE<222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 241 Xaa Arg Leu Lys Lys Arg Arg Xaa Arg Tyr Arg Val Xaa Pro 15 10 <210> SEQ ID NO 242 <211> LENGTH: 14 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (1)..(1) <223> OTHER INFORMATION:Xaa is 4Cl-Phe (L-4-chlorophenylalanine) <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (8)..(8) <223> OTHER INFORMATION: Xaa isBip [L-(4-phenyl)phenylalanine] <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 242 Xaa Trp Leu Lys Lys Arg Arg Xaa Lys Tyr ArgVal Xaa Pro 1 5 10 <210> SEQ ID NO 243 <211> LENGTH: 14 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Description of Artificial Sequence: Cyclic peptide <220>FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (1)..(1) <223>OTHER INFORMATION: Xaa is aCl-Phe (L-4-chlorophenylalanine) <220>FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (8)..(8) <223>OTHER INFORMATION: Xaa is Bip [L-(4-phenyl)phenylalanine] <220> FEATURE:<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHERINFORMATION: Xaa is D-Pro <400> SEQUENCE: 243 Xaa Trp Leu Arg Lys ArgArg Xaa Lys Tyr Arg Val Xaa Pro 1 5 10 <210> SEQ ID NO 244 <211> LENGTH:14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Cyclicpeptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:(1)..(1) <223> OTHER INFORMATION: Xaa is 4Cl-Phe(L-4-chlorophenylalanine) <220> FEATURE: <221> NAME/KEY: MISC_FEATURE<222> LOCATION: (8)..(8) <223> OTHER INFORMATION: Xaa is Bip[L-(4-phenyl)phenylalanine] <220> FEATURE: <221> NAME/KEY: MISC_FEATURE<222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 244 Xaa Trp Leu Lys Lys Arg Arg Xaa Arg Tyr Arg Val Xaa Pro 15 10 <210> SEQ ID NO 245 <211> LENGTH: 14 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (1)..(1) <223> OTHER INFORMATION:Xaa is 4Cl-Phe (L-4-chlorophenylalanine) <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (8)..(8) <223> OTHER INFORMATION: Xaa isBip [L-(4-phenyl)phenylalanine] <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (10)..(10) <223> OTHER INFORMATION: Xaa isBip [L-(4-phenyl)phenylalanine] <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 245 Xaa Trp Leu Arg Lys Arg Arg Xaa Lys Xaa ArgVal Xaa Pro 1 5 10 <210> SEQ ID NO 246 <211> LENGTH: 14 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Description of Artificial Sequence: Cyclic peptide <220>FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (1)..(1) <223>OTHER INFORMATION: Xaa is 4Cl-Phe (L-4-chlorophenylalanine) <220>FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (8)..(8) <223>OTHER INFORMATION: Xaa is Bip [L-(4-phenyl)phenylalanine] <220> FEATURE:<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (10)..(10) <223> OTHERINFORMATION: Xaa is Bip [L-(4-phenyl)phenylalanine] <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHERINFORMATION: Xaa is D-Pro <400> SEQUENCE: 246 Xaa Trp Leu Lys Lys ArgArg Xaa Arg Xaa Arg Val Xaa Pro 1 5 10 <210> SEQ ID NO 247 <211> LENGTH:14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Cyclicpeptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:(13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 247 LeuArg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Gly 1 5 10 <210> SEQ IDNO 248 <211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <223> OTHER INFORMATION: Description ofArtificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 248 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr ArgVal Xaa Arg 1 5 10 <210> SEQ ID NO 249 <211> LENGTH: 14 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Description of Artificial Sequence: Cyclic peptide <220>FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223>OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 249 Leu Arg Leu Lys LysArg Arg Trp Lys Tyr Arg Val Xaa Tyr 1 5 10 <210> SEQ ID NO 250 <211>LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:Cyclic peptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 250 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Phe 15 10 <210> SEQ ID NO 251 <211> LENGTH: 14 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHERINFORMATION: Xaa is D-Pro <400> SEQUENCE: 251 Leu Arg Leu Lys Lys ArgArg Trp Lys Tyr Arg Val Xaa Trp 1 5 10 <210> SEQ ID NO 252 <211> LENGTH:14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Cyclicpeptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:(13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 252 LeuArg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Leu 1 5 10 <210> SEQ IDNO 253 <211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <223> OTHER INFORMATION: Description ofArtificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 253 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr ArgVal Xaa Ile 1 5 10 <210> SEQ ID NO 254 <211> LENGTH: 14 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Description of Artificial Sequence: Cyclic peptide <220>FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223>OTHER INFORMATION: Xaa is D-Pro <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (14)..(14) <223> OTHER INFORMATION: Xaa isCha (L-cyclohexylalanine) <400> SEQUENCE: 254 Leu Arg Leu Lys Lys ArgArg Trp Lys Tyr Arg Val Xaa Xaa 1 5 10 <210> SEQ ID NO 255 <211> LENGTH:14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Cyclicpeptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:(13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (14)..(14) <223> OTHERINFORMATION: Xaa is 2-Nal (L-2-naphthylalanine) <400> SEQUENCE: 255 LeuArg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Xaa 1 5 10 <210> SEQ IDNO 256 <211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <223> OTHER INFORMATION: Description ofArtificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa isD-Pro <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:(14)..(14) <223> OTHER INFORMATION: Xaa is 4-(n-hexylcarbonylamino)-Pro<400> SEQUENCE: 256 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val XaaXaa 1 5 10 <210> SEQ ID NO 257 <211> LENGTH: 14 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHERINFORMATION: Xaa is D-Pro <220> FEATURE: <221> NAME/KEY: MISC_FEATURE<222> LOCATION: (14)..(14) <223> OTHER INFORMATION: Xaa is4-(n-heptylcarbonylamino)-Pro <400> SEQUENCE: 257 Leu Arg Leu Lys LysArg Arg Trp Lys Tyr Arg Val Xaa Xaa 1 5 10 <210> SEQ ID NO 258 <211>LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:Cyclic peptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <220>FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (14)..(14) <223>OTHER INFORMATION: Xaa is 4-(4-phenylbenzylcarbonylamino)-Pro <400>SEQUENCE: 258 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Xaa 15 10 <210> SEQ ID NO 259 <211> LENGTH: 14 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHERINFORMATION: Xaa is D-Pro <220> FEATURE: <221> NAME/KEY: MISC_FEATURE<222> LOCATION: (14)..(14) <223> OTHER INFORMATION: Xaa is4-(diphenylmethylcarbonylamino)-Pro <400> SEQUENCE: 259 Leu Arg Leu LysLys Arg Arg Trp Lys Tyr Arg Val Xaa Xaa 1 5 10 <210> SEQ ID NO 260 <211>LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:Cyclic peptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <220>FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (14)..(14) <223>OTHER INFORMATION: Xaa is 4-(3-aminopropylcarbonylamino)-Pro <400>SEQUENCE: 260 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Xaa 15 10 <210> SEQ ID NO 261 <211> LENGTH: 14 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHERINFORMATION: Xaa is D-Pro <220> FEATURE: <221> NAME/KEY: MISC_FEATURE<222> LOCATION: (14)..(14) <223> OTHER INFORMATION: Xaa is4-(5-aminopentylcarbonylamino)-Pro <400> SEQUENCE: 261 Leu Arg Leu LysLys Arg Arg Trp Lys Tyr Arg Val Xaa Xaa 1 5 10 <210> SEQ ID NO 262 <211>LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:Cyclic peptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <220>FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (14)..(14) <223>OTHER INFORMATION: Xaa is 4-(methylcarbonylamino)-Pro <400> SEQUENCE:262 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Xaa 1 5 10 <210>SEQ ID NO 263 <211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Descriptionof Artificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa isD-Pro <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:(14)..(14) <223> OTHER INFORMATION: Xaa is 4-(ethylcarbonylamino)-Pro<400> SEQUENCE: 263 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val XaaXaa 1 5 10 <210> SEQ ID NO 264 <211> LENGTH: 14 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHERINFORMATION: Xaa is D-Pro <220> FEATURE: <221> NAME/KEY: MISC_FEATURE<222> LOCATION: (14)..(14) <223> OTHER INFORMATION: Xaa is4-(isopropylcarbonylamino)-Pro <400> SEQUENCE: 264 Leu Arg Leu Lys LysArg Arg Trp Lys Tyr Arg Val Xaa Xaa 1 5 10 <210> SEQ ID NO 265 <211>LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:Cyclic peptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <220>FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (14)..(14) <223>OTHER INFORMATION: Xaa is 4-(isobutylcarbonylamino)-Pro <400> SEQUENCE:265 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Xaa 1 5 10 <210>SEQ ID NO 266 <211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Descriptionof Artificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa isD-Pro <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:(14)..(14) <223> OTHER INFORMATION: Xaa is 4-(n-propylcarbonylamino)-Pro<400> SEQUENCE: 266 Leu Arg Leu Leu Lys Arg Arg Trp Lys Tyr Arg Val XaaXaa 1 5 10 <210> SEQ ID NO 267 <211> LENGTH: 14 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHERINFORMATION: Xaa is D-Pro <220> FEATURE: <221> NAME/KEY: MISC_FEATURE<222> LOCATION: (14)..(14) <223> OTHER INFORMATION: Xaa is4-(cyclohexylcarbonylamino)-Pro <400> SEQUENCE: 267 Leu Arg Leu Lys LysArg Arg Trp Lys Tyr Arg Val Xaa Xaa 1 5 10 <210> SEQ ID NO 268 <211>LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:Cyclic peptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <220>FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (14)..(14) <223>OTHER INFORMATION: Xaa is 4-(cyclohexylmethylcarbonylamino)-Pro <400>SEQUENCE: 268 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Xaa 15 10 <210> SEQ ID NO 269 <211> LENGTH: 14 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHERINFORMATION: Xaa is D-Pro <220> FEATURE: <221> NAME/KEY: MISC_FEATURE<222> LOCATION: (14)..(14) <223> OTHER INFORMATION: Xaa is4-(n-butylcarbonylamino)-Pro <400> SEQUENCE: 269 Leu Arg Leu Lys Lys ArgArg Trp Lys Tyr Arg Val Xaa Xaa 1 5 10 <210> SEQ ID NO 270 <211> LENGTH:14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Cyclicpeptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:(13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (14)..(14) <223> OTHERINFORMATION: Xaa is 4-(phenylcarbonylamino)-Pro <400> SEQUENCE: 270 LeuArg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Xaa 1 5 10 <210> SEQ IDNO 271 <211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <223> OTHER INFORMATION: Description ofArtificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa isD-Pro <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:(14)..(14) <223> OTHER INFORMATION: Xaa is 4-(benzylcarbonylamino)-Pro<400> SEQUENCE: 271 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val XaaXaa 1 5 10 <210> SEQ ID NO 272 <211> LENGTH: 14 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHERINFORMATION: Xaa is D-Pro <220> FEATURE: <221> NAME/KEY: MISC_FEATURE<222> LOCATION: (14)..(14) <223> OTHER INFORMATION: Xaa is4-(3-indolylmethyl)-Pro <400> SEQUENCE: 272 Leu Arg Leu Lys Lys Arg ArgTrp Lys Tyr Arg Val Xaa Xaa 1 5 10 <210> SEQ ID NO 273 <211> LENGTH: 14<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: Description of Artificial Sequence: Cyclic peptide<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13)<223> OTHER INFORMATION: Xaa is D-Pro <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (14)..(14) <223> OTHER INFORMATION: Xaa is4-[2-(3-indolyl)ethyl]-Pro <400> SEQUENCE: 273 Leu Arg Leu Lys Lys ArgArg Trp Lys Tyr Arg Val Xaa Xaa 1 5 10 <210> SEQ ID NO 274 <211> LENGTH:14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Cyclicpeptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:(13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (14)..(14) <223> OTHERINFORMATION: Xaa is 4-(4-phenylphenyl)-Pro <400> SEQUENCE: 274 Leu ArgLeu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Xaa 1 5 10 <210> SEQ ID NO275 <211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Description of ArtificialSequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE<222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <220>FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (14)..(14) <223>OTHER INFORMATION: Xaa is 4-(n-nonylcarbonylamino)-Pro <400> SEQUENCE:275 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Xaa 1 5 10 <210>SEQ ID NO 276 <211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Descriptionof Artificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 276 Leu Arg Leu Lys Lys Gly Arg Trp Lys Tyr ArgVal Xaa Pro 1 5 10 <210> SEQ ID NO 277 <211> LENGTH: 13 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Description of Artificial Sequence: Template-fixedpeptidomimetic incorporating chain of 12 amino acid residues <220>FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223>OTHER INFORMATION: Xaa is divalent radical of 5-aminomethyl-9,9-dimethyl-3,6-dimethoxyxanthene-4-acetic acid <400> SEQUENCE: 277 LeuArg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa 1 5 10 <210> SEQ ID NO278 <211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Description of ArtificialSequence: Cyclic peptide FEATURE: <221> NAME/KEY: MISC_FEATURE <222>LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 278 Leu Tyr Leu Lys Lys Arg Arg Trp Lys Tyr Tyr Val Xaa Pro 15 10 <210> SEQ ID NO 279 <211> LENGTH: 14 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHERINFORMATION: Xaa is D-Pro <400> SEQUENCE: 279 Leu Trp Leu Lys Lys ArgArg Trp Lys Tyr Tyr Val Xaa Pro 1 5 10 <210> SEQ ID NO 280 <211> LENGTH:14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Cyclicpeptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:(13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 280 ArgTrp Leu Lys Lys Arg Arg Trp Lys Tyr Trp Val Xaa Pro 1 5 10 <210> SEQ IDNO 281 <211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <223> OTHER INFORMATION: Description ofArtificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 281 Arg Trp Leu Lys Lys Arg Arg Trp Lys Tyr TyrVal Xaa Pro 1 5 10 <210> SEQ ID NO 282 <211> LENGTH: 14 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Description of Artificial Sequence: Cyclic peptide <220>FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223>OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 282 Leu Trp Leu Lys LysArg Arg Trp Lys Tyr Tyr Arg Xaa Pro 1 5 10 <210> SEQ ID NO 283 <211>LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:Cyclic peptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 283 Leu Trp Leu Lys Lys Arg Arg Trp Lys Tyr Tyr Arg Xaa Pro 15 10 <210> SEQ ID NO 284 <211> LENGTH: 14 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHERINFORMATION: Xaa is D-Pro <400> SEQUENCE: 284 Arg Trp Leu Lys Lys ArgArg Trp Lys Tyr Tyr Arg Xaa Pro 1 5 10 <210> SEQ ID NO 285 <211> LENGTH:14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Cyclicpeptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:(6)..(6) <223> OTHER INFORMATION: Xaa is Y(Bzl) [L-O-benzylserine] <220>FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223>OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 285 Leu Arg Leu Lys LysXaa Arg Trp Lys Tyr Arg Val Xaa Pro 1 5 10 <210> SEQ ID NO 286 <211>LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:Cyclic peptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>LOCATION: (6)..(6) <223> OTHER INFORMATION: Xaa is D-Y(Bzl)[D-O-benzylserine] <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 286 Leu Arg Leu Lys Lys Xaa Arg Trp Lys Tyr Arg Val Xaa Pro 15 10 <210> SEQ ID NO 287 <211> LENGTH: 14 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (1)..(1) <223> OTHER INFORMATION:Xaa is Bip [L-(4-phenyl)phenylalanine] <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 287 Xaa Trp Leu Lys Lys Arg Arg Trp Lys Tyr TyrArg Xaa Pro 1 5 10 <210> SEQ ID NO 288 <211> LENGTH: 14 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Description of Artificial Sequence: Cyclic peptide <220>FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223>OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 288 Thr Trp Leu Lys LysArg Arg Trp Lys Tyr Tyr Arg Xaa Pro 1 5 10 <210> SEQ ID NO 289 <211>LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:Cyclic peptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa is Bip[L-(4-phenyl)phenylalanine] <220> FEATURE: <221> NAME/KEY: MISC_FEATURE<222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 289 Arg Xaa Leu Lys Lys Arg Arg Trp Lys Tyr Tyr Arg Xaa Pro 15 10 <210> SEQ ID NO 290 <211> LENGTH: 14 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHERINFORMATION: Xaa is D-Pro <400> SEQUENCE: 290 Arg Thr Leu Lys Lys ArgArg Trp Lys Tyr Tyr Arg Xaa Pro 1 5 10 <210> SEQ ID NO 291 <211> LENGTH:14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Cyclicpeptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:(13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 291 ArgTrp Thr Lys Lys Arg Arg Trp Lys Tyr Tyr Arg Xaa Pro 1 5 10 <210> SEQ IDNO 292 <211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <223> OTHER INFORMATION: Description ofArtificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 292 Arg Trp Leu Arg Lys Arg Arg Trp Lys Tyr TyrArg Xaa Pro 1 5 10 <210> SEQ ID NO 293 <211> LENGTH: 14 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Description of Artificial Sequence: Cyclic peptide <220>FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223>OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 293 Arg Trp Leu Gln LysArg Arg Trp Lys Tyr Tyr Arg Xaa Pro 1 5 10 <210> SEQ ID NO 294 <211>LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:Cyclic peptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 294 Lys Trp Leu Lys Lys Arg Arg Trp Lys Tyr Tyr Arg Xaa Pro 15 10 <210> SEQ ID NO 295 <211> LENGTH: 14 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHERINFORMATION: Xaa is D-Pro <400> SEQUENCE: 295 Tyr Trp Leu Lys Lys ArgArg Trp Lys Tyr Tyr Arg Xaa Pro 1 5 10 <210> SEQ ID NO 296 <211> LENGTH:14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Cyclicpeptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:(13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 296 TrpTrp Leu Lys Lys Arg Arg Trp Lys Tyr Tyr Arg Xaa Pro 1 5 10 <210> SEQ IDNO 297 <211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <223> OTHER INFORMATION: Description ofArtificial Sequence: Cyclic peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 297 Val Trp Leu Lys Lys Arg Arg Trp Lys Tyr TyrArg Xaa Pro 1 5 10 <210> SEQ ID NO 298 <211> LENGTH: 14 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Description of Artificial Sequence: Cyclic peptide <220>FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223>OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 298 Gln Trp Leu Lys LysArg Arg Trp Lys Tyr Tyr Arg Xaa Pro 1 5 10 <210> SEQ ID NO 299 <211>LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:Cyclic peptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>LOCATION: (1)..(1) <223> OTHER INFORMATION: Xaa is Cha(L-cyclohexylalanine) <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <400>SEQUENCE: 299 Xaa Trp Leu Lys Lys Arg Arg Trp Lys Tyr Tyr Arg Xaa Pro 15 10 <210> SEQ ID NO 300 <211> LENGTH: 14 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Cyclic peptide <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (1)..(1) <223> OTHER INFORMATION:Xaa is Y(Bzl) [L-O-benzylserine] <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa isD-Pro <400> SEQUENCE: 300 Xaa Trp Leu Lys Lys Arg Arg Trp Lys Tyr TyrArg Xaa Pro 1 5 10 <210> SEQ ID NO 301 <211> LENGTH: 14 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Description of Artificial Sequence: Linear side-chainprotected peptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>LOCATION: (1)..(1) <223> OTHER INFORMATION: Xaa is Arg(Pbf) <220>FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (2)..(2) <223>OTHER INFORMATION: Xaa is Lys(Boc) <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (3)..(3) <223> OTHER INFORMATION: Xaa isLys(Boc) <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:(4)..(4) <223> OTHER INFORMATION: Xaa is Cys(Acm) <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (5)..(5) <223> OTHER INFORMATION:Xaa is Arg(Pbf) <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>LOCATION: (8)..(8) <223> OTHER INFORMATION: Xaa is D-Pro <220> FEATURE:<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (11)..(11) <223> OTHERINFORMATION: Xaa is Cys(Acm) <220> FEATURE: <221> NAME/KEY: MISC_FEATURE<222> LOCATION: (12)..(12) <223> OTHER INFORMATION: Xaa is Lys(Boc)<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13)<223> OTHER INFORMATION: Xaa is Trp(Boc) <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (14)..(14) <223> OTHER INFORMATION: Xaa isArg(Pbf) <400> SEQUENCE: 301 Xaa Xaa Xaa Xaa Xaa Leu Pro Xaa Val Arg XaaXaa Xaa Xaa 1 5 10 <210> SEQ ID NO 302 <211> LENGTH: 14 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Description of Artificial Sequence: Cyclic peptide <220>FEATURE: <221> NAME/KEY: DISULFID <222> LOCATION: (3)..(10) <220>FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223>OTHER INFORMATION: Xaa is D-Pro <400> SEQUENCE: 302 Leu Arg Cys Lys LysArg Arg Trp Lys Cys Arg Val Xaa Pro 1 5 10 <210> SEQ ID NO 303 <211>LENGTH: 13 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:Linear side-chain protected peptide <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (1)..(1) <223> OTHER INFORMATION: Xaa isArg(Pbf) <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:(2)..(2) <223> OTHER INFORMATION: Xaa is Trp(Boc) <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (3)..(3) <223> OTHER INFORMATION:Xaa is Lys(Boc) <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>LOCATION: (4)..(4) <223> OTHER INFORMATION: Xaa is Tyr(tBu) <220>FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (5)..(5) <223>OTHER INFORMATION: Xaa is Arg(Pbf) <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (6)..(6) <223> OTHER INFORMATION: Xaa isD-Pro <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:(7)..(7) <223> OTHER INFORMATION: Xaa is 4-AllocNH-1-Fmoc_pro <220>FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (9)..(9) <223>OTHER INFORMATION: Xaa is Arg(Pbf) <220> FEATURE: <221> NAME/KEY:MISC_FEATURE <222> LOCATION: (11)..(11) <223> OTHER INFORMATION: Xaa isLys(Boc) <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:(12)..(12) <223> OTHER INFORMATION: Xaa is Lys(Boc) <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHERINFORMATION: Xaa is Arg(PbF) <400> SEQUENCE: 303 Xaa Xaa Xaa Xaa Xaa XaaXaa Leu Xaa Leu Xaa Xaa Xaa 1 5 10 <210> SEQ ID NO 304 <211> LENGTH: 14<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: Description of Artificial Sequence: Dimerictemplate-fixed peptidomimetics incorporating two chains of 12 amino acidresidues <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:(13)..(13) <223> OTHER INFORMATION: Xaa is D-Pro <220> FEATURE: <221>NAME/KEY: MISC_FEATURE <222> LOCATION: (14)..(14) <223> OTHERINFORMATION: Xaa is 4-amino-Pro, linked via CO-trimethylene- CO toanother 4-amino-Pro as member of cyclic Leu Arg Leu Lys Lys Arg Arg TrpLys Tyr Arg Val D-Pro 4-amino-Pro <400> SEQUENCE: 304 Leu Arg Leu LysLys Arg Arg Trp Lys Tyr Arg Val Xaa Xaa 1 5 10

1. Compounds of the general formulae

wherein

is a group of one of the formulae

wherein is the residue of an L-α-amino acid with B being a residue offormula —NR²⁰CH(R⁷¹)— or the enantiomer of one of the groups A1 to A69as defined hereinafter,

is a group of one of the formulae

R¹ is H; lower alkyl; or aryl-lower allyl; R² is H; alkyl; alkenyl;—(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)—C₆H₄R⁸; R³ is H;alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R⁴ is H;alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(p)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(p)(C₁)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(p)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(p)(CHR⁵⁶)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R⁵ isalkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(o)(CHR⁶¹)_(s)R⁵⁶;—(CH₂)_(o)(CHR⁶¹)_(so)NR³³R³⁴; —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(o)(CHR⁶¹)_(s) SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R⁶ is H;alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁵⁵; —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R⁷ isalkyl; alkenyl; —(CH₂)_(q)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(q)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(q)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(q)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(r)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(r)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(r)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(r)(CHR⁶¹)_(s)SO₂SR⁶²; or—(CH₂)_(r)(CHR⁶¹), C₆H₄R⁸; R⁸ is H; Cl; F; CF₃; NO₂; lower alkyl; loweralkenyl; aryl; aryl-lower alkyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;—(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)NR³³R³⁴;—(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or(CH₂)_(o)(CHR⁶¹)_(s)COR⁶⁴; R⁹ is alkyl; alkenyl;—(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁵⁵; —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R¹⁰ isalkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R¹¹ is H;alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(m)(C₆₁)_(d)NR³³R³⁴;—(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or—(CH₂)_(o)(CHR⁶¹)_(s) C₆H₄R⁸; R¹² is H; alkyl; alkenyl;—(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(m)(CHR⁶¹))_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(r)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(r)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(r)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(r)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(r)(CHR⁶¹)_(s)C₆H₄R⁸; R¹³ isalkyl; alkenyl; —(CH₂)_(q)(CHR⁶¹)OR⁵⁵; —(CH₂)_(q)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(q)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(q)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(q)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(q)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(q)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(q)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(q)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(q)(CHR⁶¹)_(s)C₆H₄R⁸; R¹⁴ is H;alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(q)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(q)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(q)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(q)(CHR⁶¹)_(s)SOR⁶²; or—(CH₂)_(q)(CHR⁶¹)_(s)C₆H₄R⁸; R¹⁵ is alkyl; alkenyl;—(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R¹⁶ isalkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R¹⁷ isalkyl; alkenyl; —(CH₂)_(q)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(q)(CHR⁶¹)_(s)R⁵⁶;—(CH₂)_(q)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(q)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(q)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(q)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(q)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(q)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(q)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(q)(CHR⁶¹)_(s)C₆H₄R⁸; R¹⁸ isalkyl; alkenyl; —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(p)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(p)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(p)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(p)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R¹⁹ islower alkyl; —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(p)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(p)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(p)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(p)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; or R¹⁸ andR¹⁹ taken together can form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; R²⁰ is H; alkyl; alkenyl; oraryl-lower alkyl; R²¹ is H; alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;—(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or—(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R²² is H; alkyl; alkenyl;—(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R³; R²³ isalkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁷R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(o)PO(OR⁶⁰)₂;—(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R²⁴ isalkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(o)(CHR⁶¹)OCONR³³R⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(s)NR CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)(OR⁶⁰)₂;—(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R²⁵ is H;alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R²⁶ is H;alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R³⁴; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; or R²⁵ andR²⁶ taken together can form: —(CH₂)₂₋₆—; —(CH₂)_(r)O(CH₂)_(r)—;—(CH₂)_(r)S(CH₂)_(r)—; or —(CH₂)_(r)NR⁵⁷(CH₂)_(r)—; R²⁷ is H; allyl;alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R²⁸ isalkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)—OR⁵⁵; —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)—(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(o)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄ ⁸; R²⁹ isalkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R³⁰ is H;alkyl; alkenyl; or aryl-lower alkyl; R³¹ is H; alkyl; alkenyl;—(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(p)(CHR⁶¹)_(s)R²⁰CONR³³R⁸²;—(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or—(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R³² is H; lower alkyl; or aryl-lower alkyl;R³³ is H; alkyl, alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;—(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴R⁶³; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR⁷⁵R⁸²;—(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR⁷⁸R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COR⁶⁴;—(CH₂)_(o)(CHR⁶¹)_(s)—CONR⁵⁸R⁵⁹, —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R³⁴ is H;lower alkyl; aryl, or aryl-lower alkyl; R³³ and R³⁴ taken together canform: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; R³⁵ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;—(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(p)(CHR⁶¹)_(o)COOR⁵⁷;—(CH₂)_(p)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(p)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(p)(CHR⁶¹)_(s)C₆H₄R⁸; R³⁶ is H,alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁷⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷¹; —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(p)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(p)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(p)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or—(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R³⁷ is H; F; Br, Cl; NO₂; CF₃; lower ale;—(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(p)(CHR⁶¹)_(s)N³³R³⁴;—(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or—(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R³⁸ is H; F; Br, Cl; NO₂; CF₃; alkyl;alkenyl; —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR³⁰OCONR³³R⁸²;—(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or—(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R³⁹ is H; alkyl; alkenyl; or aryl-loweralkyl; R⁴⁰ is H; alkyl; alkenyl; or aryl-lower alkyl; R⁴¹ is H; F; Br,Cl; NO₂; CF₃; alkyl; alkenyl; —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵;—(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(p)(CHR⁶¹)_(p)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R⁴² is H;F; Br; Cl; NO₂; CF₃; alkyl; alkenyl; —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵;—(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³⁵R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁸R⁵⁹;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R⁴³ is H;alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or—(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R⁴⁴ is alkyl; alkenyl;—(CH₂)_(r)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(r)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(r)CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(s)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(s)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(s)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(s)(CHR⁶¹)_(s)C₆H₄R⁸; R⁴⁵ is H;alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(s)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(s)(CHR⁶¹)_(s)C₆H₄R⁸; R⁴⁶ is H;alkyl; alkenyl; or —(CH₂)_(o)(CHR⁶¹)_(p)C₄H₄R⁸; R⁴⁷ is H; alkyl;alkenyl; or —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵; R⁴⁸ is H; lower allyl; loweralkenyl; or aryl-lower alkyl; R⁴⁹ is H; alkyl; alkenyl;(CHR⁶¹)_(s)COOR⁵⁷; (CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; (CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CHR⁶¹)_(s)SOR⁶²; or —(CHR⁶¹)_(s)C₆H₄R⁸; R⁵⁰ is H; lower alkyl; oraryl-lower alkyl; R⁵¹ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;—(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(o)(CHR⁶¹)_(p)PO(OR⁶⁰)₂; —(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or—(CH₂)_(p)(CHR⁶¹)_(s)C₆H₄R⁸; R⁵² is H; alkyl; alkenyl;—(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(p)PO(OR⁶⁰)₂;—(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(p)(CHR⁶¹)_(s)C₆H₄R⁸; R⁵³ is H;alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R³³R⁷⁵;—(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(o)PO(OR⁶⁰)₂;—(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(p)(CHR⁶¹)_(s)C₆H₄R⁸; R⁵⁴ is H;alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R⁸²;—(CH₂)_(o)(CHR⁶¹)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁶R⁵⁹; or—(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R⁵⁵ is H; lower alkyl; lower alkenyl;aryl-lower alkyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁷;—(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴R⁶³; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR⁷⁵R⁸²;—(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR⁷⁸R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)—COR⁶⁴;—(CH₂)_(o)(CHR⁶¹)COOR⁵⁷; or R⁵⁶ is H; lower alkyl; lower alkenyl;aryl-lower alkyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁷;—(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴R⁶³; —(CH₂)_(m)(CHR⁶¹M)_(s)OCONR⁷⁵R⁸²;—(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR⁷⁸R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)—COR⁶⁴; or—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; R⁵⁷ is H; lower alkyl; lower alkenyl;aryl lower alkyl; or heteroaryl lower alkyl; R⁵⁸ is H; lower alkyl;lower alkenyl; aryl; heteroaryl; aryl-lower alkyl; or heteroaryl-loweralkyl; R⁵⁹ is H; lower alkyl; lower alkenyl; aryl; heteroaryl;aryl-lower alkyl; or heteroaryl-lower alkyl; or R⁵⁸ and R⁵⁹ takentogether can form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; R⁶⁰ is H; lower alkyl; lower alkenyl; aryl; oraryl-lower alkyl; R⁶¹ is alkyl; alkenyl; aryl; heteroaryl; aryl-loweralkyl; heteroaryl-lower alkyl; —(CH₂)_(m)OR⁵⁵; —(CH₂)_(m)NR³³R³⁴;—(CH₂)_(m)OCONR⁷⁵R⁸²; —(CH₂)_(m)N²⁰CONR⁷⁸R⁸²; —(CH₂)_(o)COOR³⁷;—(CH₂)_(o)NR⁵⁸R⁵⁹; or —(CH₂)_(o)PO(COR⁶⁰)₂; R⁶² is lower alkyl; loweralkenyl; aryl, heteroaryl; or aryl-lower alkyl; R⁶³ is H; lower alkyl;lower alkenyl; aryl, heteroaryl; aryl-lower alkyl; heteroaryl-loweralkyl; —COR⁶⁴; COOR⁵⁷; CONR⁵⁸R⁵⁹; —SO₂R⁶²; or —PO(OR⁶⁰)₂; R³⁴ and R⁶³taken together can forms: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—, —(CH₂)₂S(CH₂)₂—;or —(CH₂)₂NR⁵⁷ (CH₂)₂—; R⁶⁴ is H; lower alkyl; lower alkenyl; aryl;heteroaryl; aryl-lower alkyl; heteroaryl-lower alkyl;—(CH₂)_(p)(CHR⁶¹)_(s)OR⁶⁵; —(CH₂)_(p)(CHR⁶¹)_(s)SR⁶⁶; or—(CH₂)_(p)(CHR⁶¹)_(s)NR³⁴R⁶³; —(CH₂)_(p)(CHR⁶¹)_(s)OCONR⁷⁵R⁸²;—(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR⁷⁸R⁸²; R⁶⁵ is H; lower alkyl; loweralkenyl; aryl, aryl-lower alkyl; heteroaryl-lower alkyl; —COR⁵⁷;—COOR⁵⁷; or —CONR⁵⁸R⁵⁹; R⁶⁶ is H; lower alkyl; lower alkenyl; aryl;aryl-lower alkyl; heteroaryl-lower allyl; or —CONR⁵⁸R⁵⁹; m is 2-4; o is0-4; p is 1-4; q is 0-2; r is 1 or 2; s is 0 or 1;

independently have any of the significances defined above for

except (a1) and (a2) with B being —NR²⁰CH(R⁷¹)— and with A being A80,A81, A90, A91, A95 or A96, and except (f) and (m), but wherein R² is—(CH₂)_(m)(CHR⁶¹)_(s)O—; —(CH₂)_(m)(CHR⁶¹)_(s)S—;—(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴—; or —(CH₂)_(o)(CHR⁶¹)_(s)CO—; R³ is—(CH₂)_(m)(CHR⁶¹)_(s)O—; —(CH₂)_(m)(CHR⁶¹)_(s)S—;—(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴—; or —(CH₂)_(o)(CHR⁶¹)_(s)CO—; R⁴ is—(CH₂)_(m)(CHR⁶¹)_(s)O—; —(CH₂)_(m)(CHR⁶¹)_(s)S—;—(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴—; or —(CH₂)_(p)(CHR⁶¹)_(s)CO—; R⁵ is—(CH₂)_(o)(CHR⁶¹)_(s)O—; —(CH₂)_(o)(CHR⁶¹)_(s)S—;—(CH₂)_(o)(CHR⁶¹)_(s)NR³⁴—; or —(CH₂)_(o)(CHR⁶¹)_(s)CO—; R⁶ is—(CH₂)_(o)(CHR⁶¹)_(s)O—; —(CH₂)_(o)(CHR⁶¹)_(s)S—;—(CH₂)_(o)(CHR⁶¹)_(s)NR³⁴—; or —(CH₂)_(o)(CHR⁶¹)_(s)CO—; R⁷ is—(CH₂)_(q)(CHR⁶¹)_(s)O—; —(CH₂)_(q)(CHR⁶¹)_(s)NR³⁴—; or—(CH₂)_(r)(CHR⁶¹)_(s)CO—; R⁸ is —(CH₂)_(o)(CHR⁶¹)_(s)O—;—(CH₂)_(o)(CHR⁶¹)_(s)S—; —(CH₂)_(o)(CHR⁶¹)_(s)NR³⁴—; or—(CH₂)_(o)(CHR⁶¹)_(s)CO—; R⁹ is —(CH₂)_(o)(CHR⁶¹)_(s)O—;—(CH₂)_(o)(CHR⁶¹)_(s)S—; —(CH₂)_(o)(CHR⁶¹)_(s)NR³⁴—; or—(CH₂)_(o)(CHR⁶¹)_(s)CO—; R¹⁰ is —(CH₂)_(o)(CHR⁶¹)_(s)O—;—(CH₂)_(o)(CHR⁶¹)_(s)S; —(CH₂)_(o)(CHR⁶¹)_(s)NR³⁴—; or—(CH₂)_(o)(CHR⁶¹)_(s)CO—; R¹¹ is —(CH₂)_(m)(CHR⁶¹)_(s)O—;—(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴—; or —(CH₂)_(o)(CHR⁶¹)_(s)CO—; R¹² is—(CH₂)_(m)(CHR⁶¹)_(s)O—; —(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴—; or—(CH₂)_(r)(CHR⁶¹)_(s)CO—; R¹³ is —(CH₂)_(q)(CHR⁶¹)_(s)O—;—(CH₂)_(q)(CHR⁶¹)_(s)S—; —(CH₂)_(q)(CHR⁶¹)_(s)NR³⁴—; or—(CH₂)_(q)(CHR⁶¹)_(s)CO—; R¹⁴ is —(CH₂)_(m)(CHR⁶¹)_(s)O—;—(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴—; or (CH₂)_(q)(CHR⁶¹)_(s)CO—; R¹⁵ is—(CH₂)_(o)(CHR⁶¹)_(s)O—; —(CH₂)_(o)(CHR⁶¹)_(s)S—;—(CH₂)_(o)(CHR⁶¹)_(s)NR³⁴—; or —(CH₂)_(o)(CHR⁶¹)_(s)CO—; R¹⁶ is—(CH₂)_(o)(CHR⁶¹)_(s)O—; —(CH₂)_(o)(CHR⁶¹)_(s)S—;—(CH₂)_(o)(CHR⁶¹)_(s)NR³⁴—; or —(CH₂)_(o)(CHR⁶¹)_(s)CO—; R¹⁷ is—(CH₂)_(q)(CHR⁶¹)_(s)O—; —(CH₂)_(q)(CHR⁶¹)_(s)S—;—(CH₂)_(q)(CHR⁶¹)_(s)NR³⁴—; or —(CH₂)_(q)(CHR⁶¹)_(s)CO—; R¹⁸ is—(CH₂)_(p)(CHR⁶¹)_(s)O; —(CH₂)_(p)(CHR⁶¹)_(s)S—;—(CH₂)_(p)(CHR⁶¹)_(s)NR³⁴—; or —(CH₂)_(p)(CHR⁶¹)_(s)CO—; R¹⁹ is—(CH₂)_(p)(CHR²¹)_(s)O—; —(CH₂)_(p)(CHR⁶¹)_(s)S—;—(CH₂)_(p)(CHR⁶¹)_(s)NR³⁴—; or —(CH₂)_(p)(CHR⁶¹)_(s)CO—; R²¹ is—(CH₂)_(o)(CHR⁶¹)_(s)O—; —(CH₂)_(o)(CHR⁶¹)_(s)S—;—(CH₂)_(o)(CHR⁶¹)_(s)NR³⁴—; or —(CH₂)_(o)(CHR⁶¹)_(s)CO—; R²² is—(CH₂)_(o)(CHR⁶¹)_(s)O—; —(CH₂)_(o)(CHR⁶¹)_(s)S—;—(CH₂)_(o)(CHR⁶¹)_(s)NR³⁴—; or —(CH₂)_(o)(CHR⁶¹)_(s)CO—; R²³ is—(CH₂)_(o)(CHR⁶¹)_(s)O—; —(CH₂)_(o)(CHR⁶¹)_(s)S—;—(CH₂)_(o)(CHR⁶¹)_(s)NR³⁴—; or —(CH₂)_(o)(CHR⁶¹)_(s)CO—; R²⁴ is—(CH₂)_(o)(CHR⁶¹)_(s)O—; —(CH₂)_(o)(CHR⁶¹)_(s)S—;—(CH₂)_(o)(CHR⁶¹)_(s)NR³⁴; or —(CH₂)_(o)(CHR⁶¹)_(s)CO—; R²⁵ is—(CH₂)_(m)(CHR⁶¹)_(s)O—; —(CH₂)_(m)(CHR⁶¹)_(s)S—;—(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴—; or —(CH₂)_(o)(CHR⁶¹)_(s)CO; — R²⁶ is—(CH₂)_(m)(CHR⁶¹)_(s)O—; —(CH₂)_(m)((CHR⁶¹)_(s)S—;—(CH₂)_(m)(CHR⁶¹)_(o)NR³⁴—; or —(CH₂)_(o)(CHR⁶¹)_(s)CO—; R²⁷ is—(CH₂)_(o)(CHR⁶¹)_(s)O—; —(CH₂)_(o)(CHR⁶¹)_(s)S—;—(CH₂)_(o)(CHR⁶¹)_(s)NR³⁴—; or —(CH₂)_(o)(CHR⁶¹)_(s)CO—; R²⁸ is—(CH₂)_(m)(CHR⁶¹)_(s)O—; —(CH₂)_(m)(CHR⁶¹)_(s)S—;—(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴—; or —(CH₂)_(o)(CHR⁶¹)_(s)CO—; R²⁹ is—(CH₂)_(o)(CHR⁶¹)_(s)O—; —(CH₂)_(o)(CHR⁶¹)_(s)S—;—(CH₂)_(o)(CHR⁶¹)_(s)NR³⁴—; or —(CH₂)_(o)(CHR⁶¹)_(s)CO—; R³¹ is—(CH₂)_(p)(CHR⁶¹)_(s)O—; —(CH₂)_(p)(CHR⁶¹)_(s)S—;—(CH₂)_(p)(CHR⁶¹)_(s)NR³⁴—; or —(CH₂)_(o)(CHR⁶¹)_(s)CO—; R³³ is—(CH₂)_(m)(CHR⁶¹)_(s)O—; —(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴—; or—(CH₂)_(o)(CHR⁶¹)_(s)CO—; R³⁷ is —(CH₂)_(p)(CHR⁶¹)_(s)O—;—(CH₂)_(p)(CHR⁶¹)_(s)S—; —(CH₂)_(p)(CHR⁶¹)_(s)R³⁴—; or—(CH₂)_(o)(CHR⁶¹)_(s)CO—; R³⁸ is —(CH₂)_(p)(CHR⁶¹)_(s)O—;—(CH₂)_(p)(CHR⁶¹)_(s)S—; —(CH₂)_(p)(CHR⁶¹)_(s)NR³⁴—; or—(CH₂)_(o)(CHR⁶¹)_(s)CO—; R⁴¹ is —(CH₂)_(p)(CHR⁶¹)_(s)O—;—(CH₂)_(p)(CHR⁶¹)_(s)S—; —(CH₂)_(p)(CHR⁶¹)_(s)NR³⁴—; or—(CH₂)_(o)(CHR⁶¹)_(s)CO—; R⁴² is —(CH₂)_(p)(CHR⁶¹)_(s)O—;—(CH₂)_(p)(CHR⁶¹)_(s)S—; —(CH₂)_(p)(CHR⁶¹)_(s)NR³⁴—; or—(CH₂)_(o)(CHR⁶¹)_(s)CO—; R⁴³ is —(CH₂)_(p)(CHR⁶¹)_(s)O—;—(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴—, or —(CH₂)_(o)(CHR⁶¹)_(s)CO—; R⁴⁵ is—(CH₂)(CHR⁶¹)_(s)O—; —(CH₂)_(o)(CHR⁶¹)_(s)S—;—(CH₂)_(o)(CHR⁶¹)_(s)NR³⁴—; or —(CH₂)_(d)(CHR⁶¹)_(s)CO—; R⁴⁷ is—(CH₂)_(o)(CHR⁶¹)_(s)O—; R⁴⁹ is —(CHR⁶¹)_(s)O—; —(CHR⁶¹)_(s)S—;—(CHR⁶¹)_(s)NR³⁴—; or —(CHR⁶¹)_(s)CO—; R⁵¹ is —(CH₂)_(m)(CHR⁶¹)_(s)—;—(CH₂)_(m)(CHR⁶¹)_(s)S—; —(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴—; or—(CH₂)_(o)(CHR⁶¹)_(s)CO—; R⁵² is —(CH₂)_(m)(CHR⁶¹)_(s)O—;—(CH₂)_(m)(CHR⁶¹)_(s)S—; —(CH₂)_(m)(C₆₁)_(s)NR³⁴—; or—(CH₂)_(o)(CHR⁶¹)_(s)CO—; R⁵³ is —(CH₂)_(m)(CHR⁶¹)_(s)O—;—(CH₂)_(m)(CHR⁶¹)_(s)S—; —(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴—; or—(CH₂)_(o)(CHR⁶¹)_(s)CO—; R⁵⁴ is —(CH₂)_(m)(CHR⁶¹)_(s)O—;—(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴; or —(CH₂)_(o)(CHR⁶¹)_(s)CO—; R⁵⁵ is—(CH₂)_(m)(CHR⁶¹)_(s)O—; —(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴—; or—(CH₂)_(o)(CHR⁶¹)_(s)CO—; R⁵⁶ is —(CH₂)_(m)(CHR⁶¹)_(s)O—;—(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴—; or —(CH₂)_(o)(CHR⁶¹)_(s)CO—; R⁶⁴ is—(CH₂)_(p)(CHR⁶¹)_(s)O—; —(CH₂)_(p)(CHR⁶¹)_(s)S—; or—(CH₂)_(p)(CHR⁶¹)_(s)NR³⁴—; m, o, p, q, r and s being as defined above;with the proviso that if more than one of the substituents R² to R⁵⁹,R²¹ to R²⁹, R³¹, R³³, R³⁷, R³⁸, R⁴¹ to R⁴³, R⁴⁵, R⁴⁷, R⁴⁹, R⁵⁷ to R⁵⁶and R⁶⁴ is present, only one of these has one of the significances justmentioned whilst the other(s) has/have any of the significance(s)mentioned earlier, L is a direct bond or one of the linkers L1:—(CH₂)_(p)CHR⁶¹[X(CH₂)_(p)CHR⁶¹]_(o)—; L2:—CO(CH₂)_(p)CHR⁶¹[X(CH₂)_(p)CHR⁶¹]_(o)CO—; L3:—CONR³⁴(CH₂)_(p)CHR⁶¹[X(CH₂)_(p)CHR⁶¹]_(o)NR³⁴CO—; L4:—O(CH₂)_(p)CHR⁶¹[X(CH₂)_(p)CHR⁶¹]_(o)O—; L5:—S(CH₂)_(p)CHR⁶¹p(CH₂)_(p)CHR⁶¹]_(o)S—; L6:—NR³⁴(CH₂)_(p)CHR⁶¹[X(CH₂)_(p)CHR⁶¹]_(o)NR³⁴—; L7:—(CH₂)_(o)CHR⁶¹Y(CH₂)_(o)CHR⁶¹—; L8:—CO(CH₂)_(o)CHR⁶¹Y(CH₂)_(o)CHR⁶¹CO—; L9:—CONR³⁴(CH₂)_(o)CHR⁶¹Y(CH₂)_(o)CHR⁶¹NR³⁴CO—; L10:—O(CH₂)_(o)CHR⁶¹Y(CH₂)_(o)CHR⁶¹O—; L11:—S(CH₂)_(o)CHR⁶¹Y(CH₂)_(o)CHR⁶¹S—; L12:—NR³⁴(CH₂)_(o)CHR⁶¹Y(CH₂)_(o)CHR⁶¹NR³⁴—; L13:—CO(CH₂)_(p)CHR⁶¹[X(CH₂)_(p)CHR⁶¹]_(o)NR³⁴—; L14:—CO(CH₂)_(o)CHR⁶¹Y(CH₂)_(o)CHR⁶¹NR³⁴—; L15—NR³⁴(CH₂)_(p)CHR⁶¹[X(CH₂)_(p)CHR⁶¹]_(o)CO—; and L16—NR³⁴(CH₂)_(o)CHR⁶¹Y(CH₂)_(o)CHR⁶¹CO—; m, o, p, q, r and s being asdefined above; X being O; S; NR³⁴; —NR³²CONR³⁴—; or —OCOO—; and Y being—C₆R⁶⁷R⁶⁸R⁶⁹R⁷⁰—; R⁶⁷ being H; Cl; Br; F; NO₂; —NR³⁴COR⁵⁷; lower ally;or lower alkenyl; R⁶⁸ being H; Cl; Br; F; NO₂; —NR³⁴COR⁵⁷; lower; orlower alkenyl; R⁶⁹ being H; Cl; Br; F; NO₂; —NR³⁴COR⁵⁷; lower alkyl; orlower alkenyl; and R⁷⁰ being H; Cl; Br; F; NO₂; —NR³⁴COR⁵⁷; lower allyl;or lower alkenyl; with the proviso that at least two of R⁶⁷, R⁶⁸, R⁶⁹and R⁷⁰ are H; and with the further proviso that —(CH₂)_(m)(CHR⁶¹)_(s)O—can be combined with linker L1, L2, L3, L7, L8 or L9;—(CH₂)_(o)(CHR⁶¹)_(s)O— can be combined with linker L1, L2, L3, L7, L8or L9; —(CH₂)_(p)(CHR⁶¹)_(s)O— can be combined with linker L1, L2, L3,L7, L8 or L9; —(CH₂)_(q)(CHR⁶¹)_(s)O— can be combined with linker L1,L2, L3, L7, L8 or L9; —(CHR⁶¹)_(s)O— can be combined with linker L1, L2,L3, L7, L8 or L9; —(CH₂)_(o)(CHR⁶¹)_(s)S— can be combined with linkerL1, L2, L3, L7, L8 or L9; or can form a disulfide bond with—(CH₂)_(m)(CHR⁶¹)_(s)S—; —(CH₂)_(o)(CHR⁶¹)_(s)S—;—(CH₂)_(p)(CHR⁶¹)_(s)S—; —(CH₂)_(q)(CHR⁶¹)_(s)S—; or —(CHR⁶¹)_(s)S—;—(CH₂)_(o)(CHR⁶¹)_(s)S— can be combined with linker L1, L2, L3, L7, L8or L9; or can form a disulfide bond with —(CH₂)_(m)(CHR⁶¹)_(s)S—;—(CH₂)_(o)(CHR⁶¹)_(s)S—; —(CH₂)_(p)(CHR⁶¹)_(s)S—;—(CH₂)_(q)(CHR⁶¹)_(s)S—; or —(CHR⁶¹)_(s)S—; —(CH₂)_(q)(CHR⁶¹)_(s)S— canbe combined with linker L1, L2, L3, L7, L8 or L9; or can form adisulfide bond with —(CH₂)_(m)(CHR⁶¹)_(s)S—; —(CH₂)_(o)(CHR⁶¹)_(s)S—;—(CH₂)_(p)(CHR⁶¹)_(s)S—; —(CH₂)_(q)(CHR⁶¹)_(s)S—; or —(CHR⁶¹)_(s)S—;—(CH₂)_(q)(CHR⁶¹)_(s)S— can be combined with linker L1, L2, L3, L7, L8or L9; or can form a disulfide bond with —(CH₂)_(m)(CHR⁶¹)_(s)S—;—(CH₂)_(o)(CHR⁶¹)_(s)S—; —(CH₂)_(p)(CHR⁶¹)_(s)S—;—(CH₂)_(q)(CHR⁶¹)_(s)S—; or —(CHR⁶¹)_(s)S—; —(CHR⁶¹)_(s)S— can becombined with linker L1, L2, L3, L7, L8 or L9; or form a disulfide bondwith —(CH₂)_(m)(CHR⁶¹)_(s)S—; —(CH₂)_(o)(CHR⁶¹)_(s)S—;—(CH₂)_(p)(CHR⁶¹)_(s)S—; —(CH₂)_(q)(CHR⁶¹)_(s)S—; or —(CHR⁶¹)_(s)S—;—(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴— can be combined with linker L1, L2, L3, L7,L8 or L9; —(CH₂)_(o)(CHR⁶¹)_(s)NR³⁴— can be combined with linker L1, L2,L3, L7, L8 or L9; —(CH₂)_(p)(CHR⁶¹)_(s)NR³⁴— can be combined with linkerL1, L2, L3, L7, L8 or L9; —(CH₂)_(q)(CHR⁶¹)_(s)NR³⁴— can be combinedwith linker L1, L2, L3, L7, L8 or L9; —(CHR⁶¹)_(s)NR³⁴— can be combinedwith linker L1, L2, L3, L7, L8 or L9; —(CH₂)_(o)(CHR⁶¹)_(s)CO— can becombined with linker L4, L5, L6, L10, L11 or L12;—(CH₂)_(p)(CHR⁶¹)_(s)CO— can be combined with linker L4, L5, L6, L1, L11or L12; —(CH₂)_(q)(CHR⁶¹)_(s)CO— can be combined with linker L4, L5, L6,L10, L11 or L12; —(CH₂)_(r)(CHR⁶¹)_(s)CO— can be combined with linkerL4, L5, L6, L10, L11 or L12; —(CHR ⁶¹)_(s)CO— can be combined withlinker L4, L5, L6, L1, L11 or L12; —(CH₂)_(m)(CHR⁶¹)_(s)O— can becombined with linker L13 or L14 and the resulting combination with—(CH₂)_(m)(CHR⁶¹)_(s)CO—; —(CH₂)_(o)(CHR⁶¹)_(p)CO—;—(CH₂)_(q)(CHR⁶¹)_(s)CO—; or —(CHR⁶¹)_(s)CO—; —(CH₂)_(o)(CHR⁶¹)_(s)O—can be combined with linker L13 or L14 and the resulting combinationwith —(CH₂)_(o)(CHR⁶¹)_(s)CO—; —(CH₂)_(o)(CHR⁶¹)_(p)CO—;—(CH₂)_(q)(CHR⁶¹)_(s)CO—; or —(CHR⁶¹)_(s)CO—; —(CH₂)_(p)(CHR⁶¹)_(s)O—can be combined with linker L13 or L14 and the resulting combinationwith —(CH₂)_(o)(CHR⁶¹)_(s)CO—, —(CH₂)_(o)(CHR⁶¹)_(s)CO—;—(CH₂)_(q)(CHR⁶¹)_(s)CO—; or —(CHR⁶¹)_(s)CO—; —(CH₂)_(q)(CHR⁶¹)_(s)O—can be combined with linker L13 or L14 and the resulting combinationwith —(CH₂)_(o)(CHR⁶¹)_(s)CO—; —(CH₂)_(o)(CHR⁶¹)_(p)CO—;—(CH₂)_(q)(CHR⁶¹)_(s)CO—; or (CHR⁶¹)_(s)CO—; —(CHR⁶¹)_(s)O— can becombined with liner L13 or L14 and the resulting combination with—(CH₂)_(o)(CHR⁶¹)_(s)CO—; —(CH₂)_(o)(CHR⁶¹)_(p)CO—;—(CH₂)_(q)(CHR⁶¹)_(s)CO—; or —(CHR⁶¹¹)_(s)CO—; —(CH₂)_(m)(CHR⁶¹)_(s)S—can be combined with linker L13 or L14 and the resulting combinationwith —(CH₂)_(o)(CHR⁶¹)_(s)CO—; —(CH₂)_(o)(CHR⁶¹)_(p)CO—;—(CH₂)_(q)(CHR⁶¹)_(s)CO—; or —(CHR⁶¹)_(s)CO—; —(CH₂)_(o)(CHR⁶¹)_(s)S—can be combined with linker L13 or L14 and the resulting combinationwith —(CH₂)_(o)(CHR⁶¹)_(s)CO—; —(CH₂)_(o)(CHR⁶¹)_(p)CO—;—(CH₂)_(q)(CHR⁶¹)_(s)CO—; or —(CHR⁶¹)_(s)CO—; —(CH₂)_(p)(CHR⁶¹)_(s)S—can be combined with linker L13 or L14 and the resulting combinationwith —(CH₂)_(o)(CHR⁶¹)_(s)CO—; —(CH₂)_(q)(CHR⁶¹)_(p)CO—;—(CH₂)_(q)(CHR⁶¹)_(s)CO—; or —(CHR⁶¹)_(s)CO—; —(CH₂)_(q)(CHR⁶¹)_(s)S—can be combined with linker L13 or L14 and the resulting combinationwith —(CH₂)_(o)(CHR⁶¹)_(s)CO—; —(CH₂)_(o)(CHR⁶¹)_(p)CO—;—(CH₂)_(q)(CHR⁶¹)_(s)CO—; or —(CHR⁶¹)_(s)CO—; —(CHR⁶¹)_(s)S— can becombined with linker L13 or L14 and the resulting combination with—(CH₂)_(o)(CHR⁶¹)_(s)CO—; —(CH₂)_(o)(CHR⁶¹)_(p)CO—;—(CH₂)_(q)(CHR⁶¹)_(s)CO—; or —(CHR⁶¹)_(s)CO—; —(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴—can be combined with linker L13 or L14 and the resulting combinationwith —(CH₂)_(o)(CHR⁶¹)_(s)CO—; —(CH₂)_(o)(CHR⁶¹)_(p)CO—;—(CH₂)_(q)(CHR⁶¹)_(s)CO—; or —(CHR⁶¹)_(s)CO—; —(CH₂)_(o)(CHR⁶¹)_(s)NR³⁴—can be combined with linker L13 or L14 and the resulting combinationwith —(CH₂)_(o)(CHR⁶¹)_(s)CO—; —(CH₂)_(o)(CHR⁶¹)_(p)CO—;—(CH₂)_(q)(CHR⁶¹)_(s)CO—; or —(CHR⁶¹)_(s)CO—; —(CH₂)_(p)(CHR⁶¹)_(s)NR³⁴—can be combined with linker L13 or L14 and the resulting combinationwith —(CH₂)_(o)(CHR⁶¹)_(s)CO—; —(CH₂)_(o)(CHR⁶¹)_(p)CO—;—(CH₂)_(q)(CHR⁶¹)_(s)CO—; or —(CHR⁶¹)_(s)CO—; —(CH₂)_(q)(CHR⁶¹)_(s)NR³⁴—can be combined with linker L13 or L14 and the resulting combinationwith —(CH₂)_(o)(CHR⁶¹)_(s)CO—; —(CH₂)_(o)(CHR⁶¹)_(p)CO—;—(CH₂)_(q)(CHR⁶¹)_(s)CO—; or —(CHR⁶¹)_(s)CO—; —(CHR⁶¹)_(s)NR³⁴— can becombined with linker L13 or L14 and the resulting combination with—(CH₂)_(o)(CHR⁶¹)_(s)CO; —(CH₂)_(o)(CHR⁶¹)_(p)CO—;—(CH₂)_(q)(CHR⁶¹)_(s)CO—; or —(CHR⁶¹)_(s)CO—; —(CH₂)_(o)(CHR⁶¹)_(s)CO—can be combined with linker L1S or L16 and the resulting combinationwith —(CH₂)_(m)(CHR⁶¹)_(s)X—, —(CH₂)_(o)(CHR⁶¹)_(s)X—,—(CH₂)_(p)(CHR⁶¹)_(s)X—, —(CH)_(q)(CHR⁶¹)_(s)X—; or —(CHR⁶¹)_(s)X—;—(CH₂p(CHR⁶¹)_(s)CO— can be combined with linker L15 or L16 and theresulting combination with —(CH₂)_(m)(CHR⁶¹)_(s)X—,—(CH₂)_(o)(CHR⁶¹)_(s)X—, —(CH₂)_(p)(CHR⁶¹)_(s)X—,—(CH₂)_(q)(CHR⁶¹)_(s)X—; or —(CHR⁶¹)_(s)X—; —(CH₂)_(q)(CHR⁶¹)_(s)CO— canbe combined with linker L15 or L16 and the resulting combination with—(CH₂)_(m)(CHR⁶¹)_(s)X—, —(CH₂)_(o)(CHR⁶¹)_(s)X—,—(CH₂)_(p)(CHR⁶¹)_(s)X—, —(CH₂)_(q)(CHR⁶¹)_(s)X—; or—(CH₂)_(r)(CHR⁶¹)_(s)CO— can be combined with linker L15 or L16 and theresulting combination with —(CH₂)_(m)(CHR⁶¹)_(s)X—,—(CH₂)_(o)(CHR⁶¹)_(s)X—, —(CH₂)_(q)(CHR⁶¹)_(s)X—;—(CH₂)_(q)(CHR⁶¹)_(s)X—; or —(CHR⁶¹)_(s)X—; —(CHR⁶¹)_(s)CO— can becombined with linker L15 or L16 and the resulting combination with—(CH₂)_(m)(CHR⁶¹)_(s)X—; —(CH₂)_(o)(CHR⁶¹)_(s)X—;—(CH₂)_(p)(CHR⁶¹)_(s)X—; —(CH₂)_(q)(CHR⁶¹)_(s)X—; or —(CHR⁶¹)_(s)X; Z,Z¹ and Z² independently are chains of n α-amino acid residues, n beingan integer from 8 to 16, the positions of said amino acid residues insaid chains being counted starting from the N-terminal amino acid,whereby these amino acid residues are, depending on their position inthe chains, Gly, or Pro, or of formula -A-CO—, or of formula —B—CO—, orof one of the types C: —NR²⁰CH(R⁷²)CO—; D: —NR²⁰CH(R⁷³)CO—; E:NR²⁰CH(R⁷⁴)CO—; F: —NR²⁰CH(R⁸⁴)CO—; and H:—NR²⁰—CH(CO—)—(CH₂)₄₋₇—CH(CO—)—NR²⁰—;—NR²⁰—CH(CO—)—(CH₂)_(p)SS(CH₂)_(p)—CH(CO—)—NR²⁰—;—NR²⁰—(CH(CO—)—(—(CH₂)_(p)NR²⁰CO(CH₂)_(p)—(CH(CO—)—NR²⁰—; and—NR²⁰—CH(CO—)—(CH₂)_(p)NR²⁰CONR²⁰(CH₂)_(p)—H(CO—)—NR²⁰—; R⁷¹ is H; loweralkyl; lower alkenyl; —(CH₂)_(p)(CHR⁶¹)_(s)OR⁷⁵;—(CH₂)_(p)(CHR⁶¹)_(s)SR⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵⁷; —(CH₂)_(p)(CHR⁶¹)_(s)N²⁰CONR³³R⁸²;—(CH₂)_(o)(CHR⁶¹)_(s)COOR⁷⁵; —(CH₂)_(p)CONR⁵⁸R⁵⁹; —(CH₂)_(p)PO(OR⁶²)₂;—(CH₂)_(p)SO₁R⁶²; or —(CH₂)_(o)—C₆R⁶⁷R⁶⁸R⁶⁹R⁷⁰R⁷⁶; R⁷² is H; loweralkyl; lower alkenyl; —(CH₂)_(p)(CHR⁶¹)_(s)OR⁸⁵; or—(CH₂)_(p)(CHR⁶¹)_(s)SR⁸⁵; R⁷³ is —(CH₂)_(o)R⁷⁷;—(CH₂)_(r)O(CH₂)_(o)R⁷⁷; —(CH₂)_(r)S(CH₂)_(o)R⁷⁷; or—(CH₂)_(r)NR²⁰(CH₂)_(o)R⁷⁷; R⁷⁴ is —(CH₂)_(p)NR⁷⁸R⁷⁹; —(CH₂)_(p)NR⁷⁷R⁸⁰;—(CH₂)_(p)C(═NR⁸⁰)NR⁷⁸R⁷⁹; —(CH₂)_(p)C(═NOR⁵⁰)NR⁷⁸SR⁷⁹;—(CH₂)_(p)C(═NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹; —(CH₂)_(p)NR⁸⁰C(═NR⁸⁰)NR⁷⁸R⁷⁹;—(CH₂)_(p)N═C(NR⁷⁸R⁸⁰)NR⁷⁹R⁸⁰; —(CH₂)_(p)C₆H₄NR⁷⁸R⁷⁹;—(CH₂)_(p)C₆H₄NR⁷⁷R⁸⁰; —(CH₂)_(p)C₆H₄C(═NR⁸⁰)NR⁷⁸R⁷⁹;—(CH₂)_(p)C₆H₄C(═NOR⁵⁰)NR⁷⁸NR⁷⁹; —(CH₂)_(p)C₆H₄C(═NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹;—(CH₂)_(p)C₆H₄NR⁸⁰C(═NR⁸⁰)NR⁷⁸NR⁷⁹; —(CH₂)_(p)C₆H₄N═C(NR⁷⁸R⁸⁰)NR⁷⁹R⁸⁰;—(CH₂)_(r)O(CH₂)_(m)NR⁷⁸R⁷⁹; —(CH₂)_(r)O(CH₂)_(m)NR⁷⁷R⁸⁰;—(CH₂)_(r)O(CH₂)_(p)C(—NR⁸⁰)NR⁷⁸R⁷⁹;—(CH₂)_(r)O(CH₂)_(p)C(═NOR⁵⁰)NR⁷⁸R⁷⁹;—(CH₂)_(r)O(CH₂)_(p)C(═NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹;—(CH₂)_(r)O(CH₂)_(p)NR⁸⁰C(═NR⁸⁰)NR⁷⁸R⁷⁹;—(CH₂)_(r)O(CH₂)_(m)N═C(NR⁷⁸R⁸⁰)NR⁷⁹R⁸⁰;—(CH₂)_(r)O(CH₂)_(p)C₆H₄CNR⁷⁸R⁷⁹;—(CH₂)_(r)O(CH₂)_(p)C₆H₄C(═NR⁸⁰)NR⁷⁸R⁷⁹;—(CH₂)_(r)O(CH₂)_(p)C₆H₄C(═NOR⁵⁰)NR⁷⁸R⁷⁹;—(CH₂)_(r)—O(CH₂)_(p)C₆H₄C(═NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹;—(CH₂)_(r)O(CH₂)_(p)C₆H₄NR⁸⁰C(═NR⁸⁰)NR⁷⁸R⁷⁹; —(CH₂)_(r)S(CH₂)NR⁵⁸R⁵⁹;—(CH₂)_(r)S(CH₂)_(m)NR⁷⁷R⁸⁰; —(CH₂)_(r)S(CH₂)_(p)C(═NR⁸⁰)NR⁷⁸R⁷⁹;—(CH₂)_(r)S(CH₂)_(p)C(—NOR⁵⁰)NR⁷⁸R⁷⁹;—(CH₂)_(r)S(CH₂)_(p)C(═NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹;—(CH₂)_(r)S(CH₂)_(m)NR⁸⁰C(═NR⁸⁰)NR⁷⁸R⁷⁹;—(CH₂)_(r)S(CH₂)_(m)N═C(NR⁷⁸R⁸⁰)NR⁷⁹R⁷⁹;—(CH₂)_(r)S(CH₂)_(p)C₆H₄CNR⁷⁸R⁷⁹;—(CH₂)_(r)S(CH₂)_(p)C₆H₄C(═NR⁸⁰)NR⁷⁸R⁷⁹;—(CH₂)_(r)S(CH₂)_(p)C₆H₄C(═NOR⁵⁰)_(o)NR⁷⁸R⁷⁹;—(CH₂)_(r)S(CH₂)_(p)C₆H₄C(═NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹;—(CH₂)_(r)S(CH₂)_(p)C₆H₄NR⁸⁰C(═NR⁸⁰)NR⁷⁸R⁷⁹; —(CH₂)_(p)NR⁸⁰COR⁶⁴;—(CH₂)_(p)NR⁸⁰COR⁷⁷; —(CH₂)_(p)N⁸⁰CONR⁷⁸R⁷⁹; or—(CH₂)_(p)C₆H₄NR⁸⁰CONR⁷⁸R⁷⁹; R⁷⁵ is lower alkyl; lower alkenyl; oraryl-lower alkyl; R³³ and R⁷⁵ taken together can form: —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; R⁷⁵ and R⁸²taken together can form —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; R⁷⁶ is H; lower alkyl; lower alkenyl; aryl-loweralkyl; —(CH₂)_(o)OR⁷²; —(CH₂)_(o)SR⁷²; —(CH₂)_(o)NR³³R³⁴;—(CH₂)_(o)OCONR³³R⁷⁵; —(CH₂)_(o)NR²⁰CONR³³R⁸²; —(CH₂)_(o)COOR⁷⁵;—(CH₂)_(o)CONR⁵⁸R⁵⁹; —(CH₂)_(s)PO(OR⁶⁰)₂; —(CH₂)_(p)SO₂R⁶²; or—(CH₂)_(o)COR⁶⁴; R⁷⁷ is —C₆R⁶⁷R⁶⁸R⁶⁹R⁷⁰R⁷⁶; or a heteroaryl group of oneof the formulae

R⁷⁸ is H; lower alkyl; aryl; or aryl-lower alkyl; R⁷⁸ and R⁸² takentogether can form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; R⁷⁹ is H; lower alkyl; aryl; or aryl-lower allyl; orR⁷⁸ and R⁷⁹, taken together, can be —(CH₂)₂₋₇—; —(CH₂)₂O(CH₂)—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; R⁸⁰ is H; or lower alkyl; R⁸¹ is H; lower allyl; oraryl-lower alkyl; R⁸² is H; lower alkyl; aryl; heteroaryl; or aryl-loweralkyl; R³³ and R⁸² taken together can form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; R⁸³ is H; lower alkyl; aryl; or—NR⁷⁸R⁷⁹; R⁸⁴ is —(CH₂)_(m)(CHR⁶¹)_(s)OH; —(CH₂)_(p)CONR⁷⁸R⁷⁹;—(CH₂)_(p)NR⁸⁰CONR⁷⁸R⁷⁹; —(CH₂)_(p)C₆H₄CONR⁷⁸R⁷⁹; or —(CH₂)_(p)C₆H₄NR⁸⁰CONR⁷⁸R⁷⁹; R⁸¹ is lower alkyl; or lower alkenyl; with theproviso that in said chain(s) of n α-amino acid residues Z, Z¹ and Z² ifn is 8, the amino acid residues in positions 1 to 8 are: P1: of type Cor or of type D or of type E or of type F, or the residue is Pro; P2: oftype E or of type D or of type F; P3: of type E or of type C, or theresidue is Pro; P4: of type E or of formula -A-CO—; P5: of type E or offormula —B—CO—, or the residue is Gly; P6: of type D, or the residue isPro; P7: of type or of type C or of type D or of type E; and P8: of typeC or of type D or of type E or of type F, or the residue is Pro; or P2and P7, taken together, can form a group of type H; and at P4 and P5also D-isomers being possible; if n is 9, the amino acid residues inpositions 1 to 9 are: P1: of type C or of type D or of type E or of typeF, or the residue is Pro; P2: of type E or of type D or of type F; P3:of type C or of type D or of type E, or the residue is Pro; P4: of typeE or of type D, or the residue is Pro; P5: of type E, or the residue isGly or Pro; P6: of type D or of type E, or the residue is Gly or Pro;P7: of type E or of type D or of type C, or the residue is Pro; P8: oftype E or of type D; and P9: of type C or of type D or of type E or oftype F, or the residue is Pro; or P2 and P8, taken together, can form agroup of type H; and at P4, P5 and P6 also D-isomers being possible; ifn is 10, the amino acid residues in positions 1 to 10 are: P1: of type Cor of type D or of type E or of type F, or the residue is Pro; P2: oftype E or of type D, or the residue is Pro; P3: of type C or of type E;P4: of type E or of type D or of type F, or the residue is Pro; P5: oftype E or of type F or of formula -A-CO—, or the residue is Gly; P6: oftype E or of formula —B—CO—, or the residue is Gly; P7: of type D or oftype E, or the residue is Gly or Pro; P8: of type D or of type E; P9: oftype E or of type D or of type C, or the residue is Pro; and P10: oftype C or of type D or of type E or of type F; or P3 and P8, takentogether, can form a group of type H; and at P5 and P6 also D-isomersbeing possible; if n is 11, the amino acid residues in positions 1 to 11are: P1: of type C or of type D or of type E or of type F, or theresidue is Pro; P2: of type E or of type C or of type D; P3: of type Dor of type E, or the residue is Pro; P4: of type E or of type C or oftype F; P5: of type E or of type r, or the residue is Gly or Pro; P6: oftype E or of type F, or the residue is Gly or Pro; P7: of type E or oftype F, or the residue is Gly or Pro; P8: of type D or of type E or oftype F; P9: of type D or of type E, or the residue is Pro; P10: of typeE or of type C or of type D; and P11: of type C or of type D or of typeE or of type F, or the residue is Pro; or P4 and P8 and/or P2 and P10,taken together, can form a group of type H; and at P5, P6 and P7 alsoD-isomers being possible; if n is 12, the amino acid residues inpositions 1 to 12 are: P1: of type C or of type D or of type E or oftype F, or the residue is Pro; P2: of type E or of type D; P3: of type Cor of type D, or the residue is Pro; P4: of type E or of type F or oftype D; P5: of type E or of type D or of type C, or the residue is Glyor Pro; P6: of type E or of type F or of formula -A-CO—, or the residueis Gly; P7: of type E or of type F or of formula —B—CO—, P8: of type Dor of type C, or the residue is Pro; P9: of type E or of type D or oftype F; P10: of type D or of type C, or the residue is Pro; P11: of typeE or of type D; and P12: of type C or of type D or of type E or of typeF, or the residue is Pro; or P4 and P9 and/or P2 and P11, takentogether, can form a group of type H; and at P6 and P7 also D-isomersbeing possible; if n is 13, the amino acid residues in positions 1 to 13are: P1: of type C or of type D or of type E or of type F, or theresidue is Pro; P2: of type E or of type F or of type D; P3: of type Cor of type D or of type E, or the residue is Pro; P4: of type E of typeC or of type F; P5: of type E or of type D, or the residue is Gly orPro; P6: of type E or of type F, or the residue is Gly or Pro; P7: oftype E or of type F, or the residue is Pro; P8: of type D or of type Eor of type F, or the residue is Pro; P9: of type D or of type E, or theresidue is Pro; P10: of type E or of type C or of type F; P11: of type Cor of type E, or the residue is Pro; P12: of type E or of type D or oftype C; and P13: of type C or of type D or of type E or of type F, orthe residue is Pro; or P4 and P10 and/or P2 and P12, taken together, canform a group of type H; and at P6, P7 and P8 also D-isomers beingpossible; if n is 14, the amino acid residues in positions 1 to 14 are:P1: of type C or of type D or of type E or of type F, or the residue isPro; P2: of type E or of type C or of type D, or the residue is Pro; P3:of type C or of type D or of type E; P4: of type D or of type C or oftype E, or the residue is Pro; P5: of type B or of type D; P6: of type Eor of type F, or the residue is Gly or Pro; P7: of type E or of type For of formula -A-CO—, or the residue is Gly; P8: of type E or of type For of formula —B—CO—, or the residue is Gly; P9: of type D or of type E,or the residue is Pro; P10: of type C or of type D or of type E; P11: oftype E or of type D or of type P, or the residue is Pro; P12: of type Dor of type E; P13: of type E or of type C or of type D, or the residueis Pro; and P14: of type C or of type D or of type E or of type F, orthe residue is Pro; or P5 and P10 and/or P3 and P12, taken together, canform a group of type H; and at P7 and P8 also D-isomers being possible;if n is 15, the amino acid residues in positions 1 to 15 are: P1: oftype C or of type D or of type E or of type F, or the residue is Pro;P2: of type E or of type F or of type D; P3: of type C or of type D orof type E, or the residue is Pro; P4: of type E or of type D or of typeF; P5: of type C or of type D or of type E, or the residue is Pro; P6:of type E or of type D or of type F; P7: of type C or of type E, or theresidue is Pro; P8: of type E or of type F, or the residue is Gly orPro; P9: of type E or of type F, or the residue is Gly or Pro; P10: oftype E or of type D; P11: of type C or of type D or of type B, or theresidue is Pro; P12: of type E or of type C or of type F; P13: of type Dor of type E, or the residue is Pro; P14: of type E or of type C or oftype D; and P15: of type C or of type D or of type E or of type F, orthe residue is Pro; or P6 and P10 and/or P4 and P12 and/or P2 and P14,taken together, can form a group of type H; and at P7, P8 and P9 alsoD-isomers being possible; and if n is 16, the amino acid residues inpositions 1 to 16 are: P1: of type D, or of type E or of type C or oftype F, or the residue is Pro; P2: of type E or of type F or of type D;P3: of type C or of type D or of type E, or the residue is Pro; P4: oftype E or of type D or of type F; P5: of type D or of type C or of typeE, or the residue is Pro; P6: of type E or of type D; P7: of type. E orof type F, or the residue is Gly or Pro; P8: of type E or of type P orof formula -A-CO—, or the residue is Gly; P9: of type E or of formula—B—CO—, or the residue is Gly; P10: of type D or of type E, or theresidue is Pro; P11: of type E or of type C or of type D; P12: of type Dor of type C of of type E, or the residue is Pro; P13: of type E or oftype C or of type F; P14: of type C or of type D or of type E, or theresidue is Pro; P15: of type E or of type C or of type D; and P16: oftype-C or of type D or of type E or of type F, or the residue is Pro; orP6 and P11 and/or P4 and P13 and/or P2 and P15, taken together, can forma group of type H; and at P8 and P9 also D-isomers being possible; andpharmaceutically acceptable salts thereof.


2. Compounds according to claim 1 wherein is other than a group offormula (a2); R¹ to R¹⁹, R²¹ to R²⁹, R³¹, R³⁵ to R³⁸, R⁴¹ to R⁴⁵, R⁵¹ toR⁵⁴ and R⁷⁶ are other than —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵ or—(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; R³³, R⁵⁵, R⁵⁶, R⁶¹ and R⁶⁴ are otherthan —(CH₂)_(m)(CHR⁶¹)_(s)OCONR⁷⁵R⁸² or—(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR⁷⁸R⁸²; R³³ and R³⁴, or R³⁴ and R⁶³ areother than, taken together, —CH₂₋₆—; —(CH₂)₂O(CH₂)₂—, —(CH₂)₂S(CH₂)₂— or—(CH₂)₂NR⁵⁷(CH₂)₂—; R⁵⁷ in —(CH₂)₂NR⁵⁷(CH₂)₂— or —(CH₂)₂NR⁵⁷(CH₂)₂— isother than lower alkenyl or heteroaryl-lower alkyl; R⁷¹ is H, loweralkyl, lower alkenyl, —(CH₂)_(p)(CHR⁶¹)_(s)OR⁷⁵,—(CH₂)_(p)(CHR⁶¹)_(s)SR⁷⁵, —(CH₂)_(p)NR^(x)R^(y),—(CH₂)_(o)(CHR⁶¹)_(s)COOR⁷⁵, —(CH₂)_(p)CONR^(x)R^(y),—(CH₂)_(p)PO(OR⁶²)₂, —(CH₂)_(p)SO₂R⁶², or —(CH₂)_(o)—C₆R⁶⁷R⁶⁸R⁶⁹R⁷⁰R⁷⁶;R⁷⁴ is other than —(CH₂)_(p)NR⁷⁷R⁸⁰, —(CH₂)_(p)C₆H₄NR⁷⁷R⁸⁰,—(CH₂)_(p)O(CH₂)_(m)NR⁷⁷R⁸⁰, —(CH₂)_(p)S(CH₂)_(m)NR⁷⁷R⁸⁰,—(CH₂)_(p)N═C(NR⁷⁸R⁸⁰)NR⁷⁹R⁸⁰, —(CH₂)_(p)C₆H₄N═C(NR⁷⁸R⁸⁰)NR⁷⁹R⁸⁰,—(CH₂)_(p)O(CH₂)_(m)N═C(NR⁷⁸R⁸⁰)NR⁷⁹R⁸⁰,—(CH₂)_(p)S(CH₂)_(m)N═C(NR⁷⁸R⁸⁰)NR⁷⁹R⁸⁰, —(CH₂)_(p)NR⁸⁰COR⁶⁴, or—(CH₂)_(p)NR⁸⁰COR⁷⁷; is other than H52, H53 and H54; in Z, Z¹ or Z² if nis 8, the amino acid residues in positions 1, 7 and 8 are: P1: of type Cor of type D or of type E, or the residue is Pro; P7: of type C or oftype D; and P8: of type C or of type D or of type E, or the residue isPro; if n is 9, the amino acid residues in positions 1 and 9 are: P1: oftype C or of type D or of type E, or the residue is Pro; and P9: of typeC or of type D or of type E, or the residue is Pro; if n is 10, theamino acid residues in positions 1 and 10 are: P1: of type C or of typeD or of type E, or the residue is Pro; and P10: of type C or of type Dor of type E; if n is 11, the amino acid residues in positions 1 and 11are: P1: of type C or of type D or of type E, or the residue is Pro; andP11: of type C or of type D or of type E, or the residue is Pro; if n is12, the amino acid residues in positions 1, 5 and 12 are: P1: of type Cor of type D or of type E, or the residue is Pro; P5: of type E or oftype D, or the residue is Gly or Pro; and P12: of type C or of type D orof type E, or the residue is Pro; if n is 13, the amino acid residues inpositions 1 and 13 are: P1: of type C or of type D or of type E, or theresidue is Pro; and P13: of type C or of type D or of type E, or theresidue is Pro; if n is 14, the amino acid residues in positions 1 and14 are: P1: of type C or of type D or of type E, or the residue is Pro;and P14: of type C or of type D or of type E, or the residue is Pro; ifn is 15, the amino acid residues in positions 1 and 15 are: P1: of typeC or of type D or of type E, or the residue is Pro; and P15: of type Cor of type D or of type E, or the residue is Pro; if n is 16, the aminoacid residues in positions 1 and 16 are: P1: of type D or of type E orof type C, or the residue is Pro; and P16: of type C or of type D or oftype E, or the residue is Pro.
 3. Compounds according to claim 1 or 2wherein

is a group of formula (a1) or (a2).
 4. Compounds according to claim 3wherein A is a group of one of the formulae A1 to A69; R¹ is hydrogen orlower alkyl; R² is H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (whereR⁵⁵ is lower alkyl; or lower alkenyl); —C₂)_(m)SR⁵⁶ (where R⁵⁶ is loweralkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³ is lower alkyl;or lower alkenyl; R³⁴ is H; or lower alkyl; or R³³ and R³⁴ takentogether are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl); (CH₂)_(m)OCONR³³R⁷⁵(where R³³ is H; lower alkyl; or lower alkenyl; R⁷⁵ is lower alkyl; orR³³ and R⁷⁵ taken together are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;—(CH₂)₂S(CH₂)₂; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl);—(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰ is H; or lower alkyl; R³³ is H; orlower alkyl; or lower alkenyl; R⁸² is H; or lower alkyl; or R³³ and R⁸²taken together are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl);—(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰ is H; or lower alkyl; R⁵⁷ is loweralkyl; or lower alkenyl); (CH₂)_(o)COOR⁵⁷ (where R⁵⁷ is lower alkyl; orlower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is lower alkyl; or loweralkenyl; and R⁵⁹ is H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰ is loweralkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶² is lower alkyl; orlower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ is H; F; Cl; CF₃; loweralkyl; lower alkenyl; or lower alkoxy); R³ is H; lower alkyl; loweralkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵ is lower alkyl; or lower alkenyl);—(CH₂)_(m)SR⁵⁶ (where R⁵⁶ is lower alkyl; or lower alkenyl);—(CH₂)_(m)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl; R³⁴ is H;or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl;or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(n)NR²⁰CONR³³R⁸² (where R²⁰ isH; or lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸² is H;or lower alkyl; or R³³ and R⁸² taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰ is H; or lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ islower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is loweralkyl; or lower alkenyl; and R⁵⁹ is H; lower alkyl; or R⁵⁸ and R⁵⁹ takentogether are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)_(q)NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl);—(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰ is lower alkyl; or lower alkenyl);—(CH₂)_(o)SO₂R⁶² (where R⁶² is lower alkyl; or lower alkenyl); or—(CH₂)_(q)C₆H₄R⁸ (where R⁸ is H; F; Cl; CF₃; lower alkyl; lower alkenyl;or lower alkoxy). R⁴ is H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵(where R⁵⁵ is lower alkyl; or lower alkenyl); —(CH₂)_(m)R⁵⁶ (where R⁵⁶is lower alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³ is loweralkyl; or lower alkenyl; R³⁴ is H; or lower alkyl; or R³³ and R³⁴ takentogether are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl);—(CH₂)_(m)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl; or lower alkenyl;R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(m)CONR³³R⁸² (where R²⁰ is H; or lower alkyl;R³³ is H; or lower alkyl; or lower alkenyl; R⁸² is H; or lower alkyl; orR³³ and R⁸² taken together are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl);—(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰ is H; or lower alkyl; R⁶⁴ is loweralkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ is lower alkyl; orlower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is lower alkyl; or loweralkenyl; and R⁵⁹ is H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰ islower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶² is loweralkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ is H; F; Cl;CF₃; lower alkyl; lower alkenyl; or lower alkoxy). R⁵ is lower alkyl;lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵ is lower allyl; or loweralkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶ is lower alkyl; or lower alkenyl);—(CH₂)_(o)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl; R³⁴ is H;or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl;or lower alkenyl; R⁷⁵ is lower alkyl; or R³³and R⁷⁵ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰ isH; or lower lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸²is H; or lower alkyl; or R³³ and R⁸² taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰ is H; or lower alkyl;R⁶⁴ is alkyl; alkenyl; aryl; aryl-lower alkyl; or heteroaryl-loweralkyl); —(CH²)_(o)COOR⁵⁷ (where R⁵⁷ is lower alkyl; or lower alkenyl);—(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is lower alkyl; or lower alkenyl; and R⁵⁹is H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together are (CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰ is lower alkyl; or loweralkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶² is lower alkyl; or lower alkenyl);or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ is H; F; Cl; CF₃; lower alkyl; loweralkenyl; or lower alkoxy): R⁶ is H; lower alkyl; lower alkenyl;—(CH₂)_(o)OR⁵⁵ (where R⁵⁵ is lower alkyl; or lower alkenyl);—(CH₂)_(o)SR⁵⁶ (where R⁵⁶ is lower alkyl; or lower alkenyl);—(CH₂)_(o)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl; R³⁴ is H;or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl;or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰ isH; or lower lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸²is H; or lower alkyl; or R³³ and R⁸² taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where R²⁰ is H; or lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ islower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is loweralkyl; or lower alkenyl; and R⁵⁹ is H; or lower alkyl; or R⁵⁸ and R⁵⁹taken together are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂(where R⁶⁰ is lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (whereR⁶² is lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ isH; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy); R⁷ is loweralkyl; lower alkenyl; —(CH₂)_(q)OR⁵⁵ (where R⁵⁵ is lower alkyl; or loweralkenyl); —(CH₂)_(q)SR⁵⁶ (where R⁵⁶ is lower alkyl; or lower alkenyl);—(CH₂)_(q)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl; R³⁴ is H;or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(q)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl;or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(q)NR²⁰CONR³³R⁸² (where R²⁰ isH; or lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸² is H;or lower alkyl; or R³³ and R⁸² taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(q)N(R²⁰)COR⁶⁴ (where: R²⁰ is H; or lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); —(CH₂) COOR⁵⁷ (where R⁵⁷ is loweralkyl; or lower alkenyl); —(CH₂)_(q)CONR⁵⁸R⁵⁹ (where R⁵⁸ is lower alkyl;or lower alkenyl; and R⁵⁹ is H; or lower alkyl; or R⁵⁸ and R⁵⁹ takentogether are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl); —(CH₂)_(r)PO(OR⁶⁰)₂(where R⁶⁰ is lower alkyl; or lower alkenyl); —(CH₂)_(r)S₂R⁶² (where R⁶²is lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ is H;F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy); R⁸ is H; F;Cl; CF₃; lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵ is loweralkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶ is lower alkyl; orlower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³ is lower alkyl; or loweralkenyl; R³⁴ is H; or lower alkyl; or R³³ and R³⁴ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³ is H;or lower alkyl; or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵taken together are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl);—(CH₂)_(o)N²⁰CONR³³R⁸² (where R²⁰ is H; or lower alkyl; R³³ is H; orlower alkyl; or lower alkenyl; R⁸² is H; or lower alkyl; or R³³ and R⁸²taken together are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl);—(CH₂)_(o)N(R²⁰)COR⁶⁴ (where R²⁰ is H; or lower alkyl; R⁶⁴ is loweralkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ is lower alkyl; orlower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is lower alkyl; or loweralkenyl; and R⁵⁹ is H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰ is loweralkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶² is lower alkyl; orlower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ is H; F; Cl; CF₃; loweralkyl; lower alkenyl; or lower alkoxy); R⁹ is lower alkyl; loweralkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵ is lower alkyl; or lower alkenyl);—(CH₂)_(o)SR⁵⁶ (where R⁵⁶ is lower alkyl; or lower alkenyl);—(CH₂)_(o)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl; R³⁴ is H;or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl;or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where W is H; or lower alkyl); —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰ is H;or lower lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸² isH; or lower alkyl; or R³³ and R⁸² taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where R²⁰ is H; or lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ islower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is loweralkyl; or lower alkenyl; and R⁵⁹ is H; or lower alkyl; or R⁵⁸ and R⁵⁹taken together are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂(where R⁶⁰ is lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (whereR⁶² is lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ isH; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy); R¹⁰ islower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵ is lower alkyl; orlower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶ is lower alkyl; or loweralkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl;R³⁴ is H; or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl;or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H is or lower alkyl); —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰ isH; or lower lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸²is H; or lower alkyl; or R³³ and R⁸² taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where R²⁰ is H; or lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ islower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is loweralkyl; or lower alkenyl; and R⁵⁹ is H; lower alkyl; or R⁵⁸ and R⁵⁹ takentogether are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl); —(CH₂)—PO(OR⁶⁰)₂(where R⁶⁰ is lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (whereR⁶² is lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ isH; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy); R¹¹ is H;lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵ is lower alkyl; orlower alkenyl); —(CH₂)_(m)SR⁵⁶ (where R⁵⁶ is lower alkyl; or loweralkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl;R³⁴ is H; or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl;or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together ar—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰ isH; or lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸² is H;or lower alkyl; or R³³ and R⁸² taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—, or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where R²⁰ is H; or lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ islower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁷ is loweralkyl; or lower alkenyl; and R⁵⁹ is H; lower alkyl; or R⁵⁸ and R⁵⁹ takentogether are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂(where R⁶¹ is lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (whereR⁶² is lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ isH; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy); R¹² is H;lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵ is lower alkyl; orlower alkenyl); —(CH₂)_(m)SR⁵⁶ (where R⁵⁶ is lower alkyl; or loweralkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl;R³⁴ is H; or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl;or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰ isH; or lower lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸²is H; or lower alkyl; or R³³ and R⁸² taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰ is H; or lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); —(CH₂)_(r)COOR⁵⁷ (where R⁵⁷ islower alkyl; or lower alkenyl); —(CH₂)_(r)CONR⁵⁸R⁵⁹ (where R⁵⁸ is loweralkyl; or lower alkenyl; and R⁵⁹ is H; or lower alkyl; or R⁵⁸ and R⁵⁹taken together are (CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl); —(CH₂)_(r)PO(OR⁶⁰)₂(where R⁶⁰ is lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (whereR⁶² is lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ isH; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy): R¹³ islower alkyl; lower alkenyl; —(CH₂)_(q)OR⁵⁵ (where R⁵⁵ isis lower alkyl;or lower alkenyl); —(CH₂)_(q)SR⁵⁶ (where R⁵⁶ is lower alkyl; or loweralkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl;R³⁴ is H; or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(q)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl;or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(q)NR²⁰CONR³³R⁸² (where R²⁰ isH; or lower lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸²is H; or lower alkyl; or R³³ and R⁸² taken together are —(CH)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)₂N(R²⁰)COR⁶⁴ (where: R²⁰ is H; or lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); CH₂)_(r)COOR⁵⁷ (where R⁵⁷ islower alkyl; or lower alkenyl); —(CH₂)_(q)CONR⁵⁸R⁵⁹ (where R⁵⁸ is loweralkyl; or lower alkenyl; and R⁵⁹ is H; or lower alkyl; or R⁵⁸ and R⁵⁹taken together are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl); —(CH₂)_(r)PO(OR⁶⁰)₂(where R⁶⁰ is lower alkyl; or lower alkenyl); —(CH₂)_(r)SO₂R⁶² (whereR⁶² is lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ isH; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy); R¹⁴ is H;lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵ is lower alkyl; orlower alkenyl); —(CH₂)_(m)R⁵⁶ (where R⁵⁶ is lower alkyl; or loweralkenyl); —(CH₂)_(m)R³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl;R³⁴ is H; or lower allyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁷⁵ is H;or lower alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl;or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰ isH; or lower lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl isR⁸²: H; or lower alkyl; or R³³ and R⁸² taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰ is H; lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ islower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is loweralkyl; or lower alkenyl; and R⁵⁹ is H; or lower allyl; or R⁵⁸ and R⁵⁹taken together are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower allyl); —(CH₂)_(o)PO(OR⁶⁰)₂(where R⁶⁰ is lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (whereR⁶² is lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ isH; P; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy); R¹⁵ islower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵ is lower alkyl; orlower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶ is lower alkyl; or loweralkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl;R³⁴ is H; or lower allyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl;or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰ isH; or lower lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸²is H; or lower alkyl; or R³³ and R⁸² taken together are —(CH₂)₂₋₆—,—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where R²⁰ is H; or lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); —NR₂₀CO lower alkyl (R²⁰═H; orlower alkyl); being particularly favoured; —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷is lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ islower alkyl, or lower alkenyl; and R⁵⁹ is H; lower alkyl; or R⁵⁸ and R⁵⁹taken together are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂(where R⁶⁰ is lower allyl; or lower alkenyl); CH₂)_(o)SO₂R⁶² (where R⁶²is lower alkyl; or lower alkenyl); or (CH₂)_(q)C₆H₄R⁸ (where R⁸ is H; F;Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy); R¹⁶ is loweralkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵ is lower alkyl; or loweralkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶ is lower alkyl; or lower alkenyl);—(CH₂)_(o)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl; R³⁴ is H;or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl;or lower alkenyl; R⁷⁵ is lower allyl; or R³³ and R⁷⁵ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰ isH; or lower lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸²is H; or lower alkyl; or R³³ and R⁸² taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where R²⁰ is H; or lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ islower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is loweralkyl; or lower alkenyl; and R⁵⁹ is H; or lower alkyl; or R⁵⁸ and R⁵⁹taken together are —(CH₂)₂—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂(where R⁶⁰ is lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (whereR⁶² is lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ isH; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy); and R¹⁷ islower alkyl; lower alkenyl; —(CH₂)_(q)OR⁵⁵ (where R⁵⁵ is lower alkyl; orlower alkenyl); —(CH₂)_(q)SR⁵⁶ (where R⁵⁶ is lower alkyl; or loweralkenyl); —(CH₂)_(q)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl;R³⁴ is H; or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(q)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl;or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(q)NR²⁰CONR³³R⁸² (where R²⁰ isH; or lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸² is H;or lower alkyl; or R³³ and R⁸² taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(q)N(R²⁰)COR⁶⁴(where: R²⁰ is H; or lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); —(CH₂)_(r)COOR⁵⁷ (where R⁵⁷ islower alkyl; or lower alkenyl); —(CH₂)_(q)CONR⁵⁸R⁵⁹ (where R⁵⁸ is loweralkyl; or lower alkenyl; and R⁵⁹ is H; lower alkyl; or R⁵⁸ and R⁵⁹ takentogether are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl); —(CH₂)_(r)PO(OR⁶⁰)₂(where R⁶⁰ is lower alkyl; or lower alkenyl); —(CH₂)_(r)SO₂R⁶² (whereR⁶² is lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ isH; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy). 5.Compounds according to claim 3 or 4 wherein A is a group of one of theformulae A5 (with R² being H); A8; A22; A25; A38 (with R² being H); A42;and A50.
 6. Compounds according to claim 5 wherein A is a group offormula

wherein R²⁰ is H or lower alkyl; and R⁶⁴ is alkyl; alkenyl; aryl;aryl-lower alkyl; or heteroaryl-lower alkyl.
 7. Compounds according toclaim 6 wherein R⁶⁴ is n-hexyl; n-heptyl; 4-(phenyl)benzyl;diphenylmethyl, 3-amino-propyl; 5-amino-pentyl; methyl; ethyl;isopropyl; isobutyl; n-propyl; cyclohexyl; cyclohexylmethyl; n-butyl;phenyl; benzyl; (3-indolyl)methyl; 2-(3-indolyl)ethyl; (4-phenyl)phenyl;or n-nonyl.
 8. Compounds according to claim 3 wherein A is a group ofone of the formulae A70 to A104; R²⁰ is H; or lower alkyl; R¹⁸ is loweralkyl; R¹⁹ is lower alkyl; lower alkenyl; —(CH₂)_(p)OR⁵⁵ (where R⁵⁵ islower alkyl; or lower alkenyl); —(CH₂)_(p)SR⁵⁶ (where R⁵⁶ is loweralkyl; or lower alkenyl); —(CH₂)_(p)NR³³R³⁴ (where R³³ is lower alkyl;or lower alkenyl; R³⁴ is H; or lower alkyl; or R³³ and R³⁴ takentogether are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—, or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl);—(CH₂)_(p)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl; or lower alkenyl;R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(p)NR²⁰CONR³³R⁸² (where R²⁰ is H; or lower loweralkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸² is H; or loweralkyl; or R³³ and R⁸² taken together are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl);—(CH₂)_(p)N(R²⁰)COR⁶⁴ (where: R²⁰ is H; or lower alkyl; R⁶⁴ is loweralkyl; or lower alkenyl); —(CH₂)_(p)COOR⁵⁷ (where R⁵⁷: lower alkyl; orlower alkenyl); —(CH₂)_(p)CONR⁵⁸R⁵⁹ (where R⁵⁸ is lower alkyl; or loweralkenyl; and R⁵⁹ is H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂NS(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰ is loweralkyl; or lower alkenyl); —(CH₂)_(p)SO₂R⁸² (where R⁶² is lower alkyl; orlower alkenyl); or (CH₂)_(o)C₆H₄R⁸ (where R⁸ is I; F; Cl; CF₃; loweralkyl; lower alkenyl; or lower alkoxy); R²¹ is H; lower alkyl; loweralkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵ is lower allyl; or lower alkenyl);—(CH₂)_(o)SR⁵⁶ (where R⁵⁶ is lower alkyl; or lower alkenyl);—(CH₂)_(o)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl; R³⁴ is H;or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl; orlower alkenyl; R⁷ is lower alkyl; or R³³ and R⁷⁸ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰ isH; or lower lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸²is H; or lower alkyl; or R³³ and R⁸² taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰ is H; or lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); —(CH₂)_(o)COR⁵⁷ (where R⁵⁷ islower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is loweralkyl, or lower alkenyl; and R⁵⁹ is H; lower alkyl; or R⁵⁸ and R⁵⁹ takentogether are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂(where R⁶⁰ is lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (whereR⁶² is lower allyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ isH; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy); R²² islower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵ is lower alkyl; orlower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶ is lower alkyl; or loweralkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl;R³⁴ is H; or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl;or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)₂NR²⁰CONR³³R⁸² (where R²⁰ is H;or lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸² is H; orlower alkyl; or R³³ and R⁸² taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where R²⁰ is H; or lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); —(CH₂)_(o)COR⁵⁷ (where R⁵⁷ islower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is loweralkyl, or lower alkenyl; and R⁵⁹ is H; lower alkyl; or R⁵⁸ and R⁵⁹ takentogether are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂(where R⁶⁰ is lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (whereR⁶² is lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ isH; F; Cl; CF; lower alkyl; lower alkenyl; or lower alkoxy); R²³ is H;lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵ is lower alkyl; orlower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶ is lower alkyl; or loweralkenyl); —(CH₂)_(o)R³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl;R³⁴ is H; or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl;or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁸ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰ isH; or lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸² is H;or lower alkyl; or R³³ and R⁸² taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰ is H; or lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); —NR²⁰CO lower alkyl (R²⁰═H; orlower alkyl) being particularly favoured; —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ islower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is lowerallyl, or lower alkenyl; and R⁵⁷ is H; lower allyl; or R⁵⁸ and R⁵⁹ takentogether are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂(where R⁶⁰ is lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (whereR⁶² is lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ isH; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy); R²⁴ islower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵ is lower alkyl; orlower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶ is lower alkyl; or loweralkenyl); —(CH₂)R³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl; R³⁴is H; or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl;or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁸ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰ isH; or lower lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸²is H; or lower alkyl; or R³³ and R⁸² taken together are —(CH₂)₂—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)N(R²⁰)COR⁶⁴ (where: R²⁰ is H; or lower alkyl; R⁶⁴is lower alkyl; or lower alkenyl); —NR²⁰CO lower alkyl (R²⁰═H; or loweralkyl) being particularly favoured; —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ is loweralkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is lower alkyl,or lower alkenyl; and R⁵⁹ is H; lower alkyl; or R⁵⁸ and R⁵⁹ takentogether are —(CH₂)₂₋₆; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂(where R⁶⁰ is lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (whereR⁶² is lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ isH; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy); R²⁵ is H;lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵ is lower alkyl; orlower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³ is lower alkyl; or loweralkenyl; R³⁴ is H; or lower alkyl; or R³³ and R³⁴ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³ is H;or lower alkyl; or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵taken together are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl);—(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰ is H; or lower alkyl; R³³ is H; orlower alkyl; or lower alkenyl; R⁸² is H; or lower alkyl; or R³³ and R⁸²taken together are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl);—(CH₂)N(R²⁰)_(m)COR⁶⁴ (where: R²⁰ is H; or lower alkyl; R⁶⁴ is loweralkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ is lower alkyl; orlower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is lower alkyl; or loweralkenyl; and R⁵⁹ is H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR(CH₂)₂—; whereR⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰ is loweralkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶² is lower alkyl; orlower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ is H; F; Cl; CF₃; loweralkyl; lower alkenyl; or lower alkoxy); R²⁶ is H; lower alkyl; loweralkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵ is lower alkyl; or lower alkenyl);—(CH₂)_(m)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl; R³⁴ is H;or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl;or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰ isH; or lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸² is H;or lower alkyl; or R³³ and R⁸² taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(m)NR²⁰COR⁶⁴ (where: R²⁰ is H; or lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ islower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is loweralkyl; or lower alkenyl; and R⁵⁹ is H; lower alkyl; or R⁵⁸ and R⁵⁹ takentogether are —(CH₂)₂—, —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂(where R⁶⁰ is lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (whereR⁶² is lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ isH; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower-alkoxy); or,alternatively, R²⁵ and R²⁶ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR³⁴(CH₂)₂—; R²⁷ is H; loweralkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵ is lower alkyl; or loweralkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶ is lower alkyl; or lower alkenyl);—(CH₂)_(o)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl; R³⁴ is H;or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl;or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰ isH; or lower lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸²is H; or lower alkyl; or R³³ and R⁸² taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where R²⁰ is H; or lower alkyl;R⁶⁴ is lower allyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ islower alkyl; or lower alkenyl); —(CH₂)_(o)OCONR⁵⁸R⁵⁹ (where R⁵⁸ is loweralkyl, or lower alkenyl; and R⁵⁹ is H; lower alkyl; or R⁵⁸ and R⁵⁹ takentogether are —(CH₂)₂₋₆; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂(where R⁶⁰ is lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (whereR⁶² is lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ isH; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy); R²⁸ islower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵ is lower alkyl; orlower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶ is lower alkyl; or loweralkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl;R³⁴ is H; or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl;or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁸ taken together are—(CH₂)₂—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; whereR⁵⁷ is H; or lower alkyl); —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰ is H; orlower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸² is H; orlower alkyl; or R³³ and R⁸² taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)N(R²⁰)COR⁶⁴(where: R²⁰ is H; or lower alkyl; R⁶⁴is lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ is loweralkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is lower alkyl,or lower alkenyl; and R⁵⁹ is H; lower alkyl; or R⁵⁸ and R⁵⁹ takentogether are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)RO(OR⁶⁰)₂(where R⁶⁰ is lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (whereR⁶² is lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ isH; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy); and R²⁹ islower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵ is lower alkyl; orlower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶ is lower alkyl; or loweralkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl;R³⁴ is H; or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl;or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰ isH; or lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸² is H;or lower alkyl; or R³³ and R⁸² taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰ is H; or lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); —NR²⁰CO lower-alkyl (R²⁰═H; orlower alkyl) being particularly favoured; —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ islower allyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is loweralkyl, or lower alkenyl; and R⁵⁹ is H; lower alkyl; or R⁵⁸ and R⁵⁹ takentogether are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂(where R⁶⁰ is lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (whereR⁶² is lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ isH; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy). 9.Compounds according to claim 8 wherein R²³, R²⁴ and R²⁹ are—NR²⁰—CO-lower alkyl where R²⁰ is H; or lower alkyl.
 10. Compoundsaccording to claim 8 or 9 wherein A is a group of one of the formulaeA74 (with R²² being H); a75; A76; A77 (with R²² being H); A78; and A79.11. Compounds according to any one of claims 3 to 10 wherein B is agroup of formula —NR²⁰CH(R⁷¹)— or an enantiomer of one of the groups A5(with R² being H); A8; A22; A25 ; A38 (with R² being H); A42; A47; andA50.
 12. Compounds according to claim 11 wherein B—CO is Ala; Arg; Asn;Cys; Gln;-Gly-His; Ile; Leu; Lys; Met; Phe; Pro; Ser; Thr; Trp; Tyr;Val; Cit; Orn; tBuA; Sar; t-BuG; 4AiPhe; 3AmPhe; 2AmPhe; Phe(mC(NH₂)═NH;Phe(pC(NH₂)═NH; Phe(mNHC(NH₂)═NH; Phe(pNHC(NH₂)═NH; Phg; Cha; C₄al;C₅al; Nle; 2-Nal; 1-Nal; 4Cl-Phe; 3Cl-Phe; 2Cl-Phe; 3,4Cl₂Phe; 4F-Phe;3F-Phe; 2F-Phe; Tic; Thi; Tza; Mso; AcLys; Dpr, A₂Bu; Dbu; Abu; Aha;Aib; Y(Bzl); Bip; S(Bzl); T(Bzl); hCha; hCys; hser, hArg; bphe; Bpa;Pip; OctG; MePhe; MeNle; MeAla; MeIIe; MeVal; or MeLeu.
 13. Compoundsaccording to claim 11 or 12 wherein B is a group, having(L)-configuration, of formula

wherein R²⁰ is H; or lower alkyl; and R⁶⁴ is alkyl; alkenyl; aryl;aryl-lower alkyl; or heteroaryl-lower alkyl.
 14. Compounds according toclaim 13 wherein R⁶⁴ is n-hexyl; n-heptyl; 4-(phenyl)benzyl;diphenylmethyl, 3-amino-propyl; 5-amino-pentyl; methyl; ethyl;isopropyl; isobutyl; n-propyl; cyclohexyl; cyclohexylmethyl; n-butyl;phenyl; benzyl; (3-indolyl)methyl; 2-3-indolyl)ethyl; (4phenyl)phenyl;or n-nonyl.
 15. Compounds according to claim 1 or 2 wherein

is a group of formula (b1) or (1); R¹ is H; or lower alkyl; R²⁰ is H; orlower alkyl; R³⁰ is H; or methyl; R³¹ is H; lower alkyl; lower alkenyl;—(CH₂)_(p)OR⁵⁵ (where R⁵⁵ is lower alkyl; or lower alkenyl);—(CH₂)_(p)R³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl; R³⁴ is H;or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(p)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl;or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(p)NR²⁰CONR³³R⁸² (where R²⁰ isH; or lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸² is H;or lower alkyl; or R³³ and R⁸² taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(p)N(R²⁰)COR⁶⁴ (where: R²⁰ is H; or lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ islower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is loweralkyl, or lower alkenyl; and R⁵⁹ is H; lower alkyl; or R⁵⁸ and R⁵⁹ takentogether are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂(where R⁶⁰ is lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (whereR⁶² is lower alkyl; or lower alkenyl); or —(CH₂)_(r)C₆H₄R⁸ (where R⁸ isH; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy); mostpreferably —(CH₂CONR⁵⁸R⁵⁹ (where R⁵⁸ is H; or lower alkyl; and R⁵⁹ islower alkyl; or lower alkenyl); R³² is H; or methyl; R³³ is lower alkyl;lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵ is lower alkyl; or loweralkenyl); —(CH₂)_(m)NR³⁴R⁶³ (where R³⁴ is lower alkyl; or lower alkenyl;R⁶³ is H; or lower alkyl; or R³⁴ and R⁶³ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(m)OCONR⁷⁵R⁸² (where R⁷⁵ is lower alkyl; orlower alkenyl; R⁸² is H; or lower alkyl; or R⁷⁵ and R⁸² taken togetherare —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—, —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(m)NR²⁰OCONR⁷⁸R⁸² (where R²⁰ isH; or lower alkyl; R⁷⁸ is H; or lower alkyl; or lower alkenyl; R⁸² is H;or lower alkyl; or R⁷⁸ and R⁸² taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰ is H; or lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ islower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is loweralkyl; or lower alkenyl; and R⁵⁹ is H; lower alkyl; or R⁵⁸ and R⁵⁹ takentogether are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); R³⁴ is H; or loweralkyl; R³⁵: is H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:lower alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³ is loweralkyl; or lower alkenyl; R³⁴ is H; or lower alkyl; or R³³ and R³⁴ takentogether are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl);—(CH₂)_(m)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl; or lower alkenyl;R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—, or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰ is H; or loweralkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸² is H; or loweralkyl; or R³³ and R⁸² taken together are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)—;—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl);—(CH₂)N(R²⁰)COR⁶⁴ (where: R²⁰ is H; or lower alkyl; R⁶⁴ is lower alkyl;or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ is lower alkyl; or loweralkenyl); —(CH₂)_(o)CONR⁵⁷R⁵⁹ (where R⁵⁸ is lower alkyl; or loweralkenyl; and R⁵⁹ is H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together are—(CH₂)₂₋₆; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); R³⁶: lower alkyl; lower alkenyl; oraryl-lower alkyl; R³⁷ is H; lower alkyl; lower alkenyl; —(CH₂)_(p)OR⁵⁵(where R⁵⁵ is lower alkyl; or lower alkenyl); —(CH₂)_(p)NR³³R³⁴ (whereR³³ is lower alkyl; or lower alkenyl; R³⁴ is H; or lower alkyl; or R³³and R³⁴ taken together are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)—;or —(CH₂)₂NR⁵⁷(CH₂)₂—, where R⁵⁷ is H; or lower alkyl);—(CH₂)_(p)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl; or lower alkenyl;R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are —(CH₂)₂₋₆;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(p)NR²⁰CONR³³R⁸² (where R²⁰ is H; or lowerallyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸² is H; or loweralkyl; or R³³ and R⁸² taken together are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl);—(CH₂)_(p)N(R²⁰)COR⁶⁴ (where: R²⁰ is H; or lower alkyl; R⁶⁴ is loweralkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ is lower alkyl; orlower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is lower alkyl, or loweralkenyl; and R⁵⁹ is H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together are—(CH₂)₂—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; whereR⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰ is loweralkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶² is lower alky; orlower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ is H; F; Cl; CF₃; loweralkyl; lower alkenyl; or lower alkoxy); and R³⁸ is H; lower allyl; loweralkenyl; —(CH₂)_(p)OR⁵⁵ (where R⁵⁵ is lower alkyl; or lower alkenyl);—(CH₂)_(p)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl; R³⁴ is H;or lower alkyl; or R³³ and R³⁴ taken together sre —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(p)NR²⁰OCONR³³R⁷⁵ (where R³³ is H; or loweralkyl; or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ takentogether are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl);—(CH₂)_(p)NR²⁰CONR³³R⁸² (where R²⁰ is H; or lower alkyl; R³³ is H; orlower alkyl; or lower alkenyl; R⁸² is H; or lower alkyl; or R³³ and R⁸²taken together are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl);—(CH₂)_(p)N(R²⁰)COR⁶⁴ (where: R²⁰ is H; or lower alkyl; R⁶⁴ is loweralkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ is lower alkyl; orlower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is lower alkyl, or loweralkenyl; and R⁵⁹ is H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷ (CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰ is loweralkyl; or lower alkenyl); —(CH₂)_(q)SO₂R⁶² (where R⁶² is lower alkyl; orlower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ is H; F; Cl; CF₃; loweralkyl; lower alkenyl; or lower alkoxy).
 16. Compounds according to claim15 wherein R¹ is H; R²⁰ is H; R³⁰ is H; R³¹ is carboxymethyl; or loweralkoxycarbonylmethyl; R³² is H; R³⁵ is methyl; R³⁶ is methoxy; R³⁷ is Hand R³⁸ is H.
 17. Compounds according to any one of claims 1 to 16wherein in the chain(s) of α-amino acid residues Z, Z¹ and Z² If n is 8,the amino acid residues in position 1-8 are: P1: of type C or of type D;or of type E; P2: of type E; or of type D; P3: of type E; P4: of type Eor of formula -A1-A69-CO—; P5: of type E or of formula —B—CO—; P6: oftype D; P7: of type E; or of type D and P8: of type C or of type D; orof type E; at P4 and P5 also D-isomers being possible; if n is 9, theamino acid residues in position 1-9 are: P1: of type C or of type D; orof type E; P2: of type E; or of type D; P3: of type C; P4: of type E, orthe residue is Pro; P5: of type E, or the residue is Pro; P6: of type Dor of type E, or the residue is Pro; P7: of type E or of type D; P8: oftype E; or of type D and P9: of type C or of type D; or of type E; atP4, P5 and P6 also D-isomers being possible; if n is 10, the amino acidresidues in position 1-10 are: P1: of type C or of type D; or of type E;P2: of type E; or of type D; P3: of type C; P4: of type E or of type D;P5: of type E or of formula -A1-A69-CO—; P6: of type E or of formula—B—CO—; P7: of type D or of type E; P8: of type D; P9: of type E; or oftype D and P10: of type C or of type D; or of type E; at P5 and P6 alsoD-isomers being possible; if n is 11, the amino acid residues inposition 1-11 are: P1: of type C or of type D; or of type E; P2: of typeE; or of type D; P3: of type D; P4: of type E or of type C; P5: of typeE, or the residue is Pro; P6: of type E, or the residue is Pro; P7: oftype E, or the residue is Pro; P8: of type D or of type E; P9: of typeD; P10: of type E; or of type D and P11: of type C or of type D; or oftype E; at P5, P6 and P7 also D-isomers being possible; if n is 12, theamino acid residues in position 1-12 are: P1: of type C or of type E; orof type D; or of type F; P2: of type E; or of type D; P3: of type C orof type D; P4: of type E; P5: of type E; or of type C; P6: of type E orof type F or of formula -A1-A69-CO—; P7: of type E or of formula —B—CO—;P8: of type D; P9: of type E or of type D; P10: of type D; P11: of typeE; or of type D and P12: of type C or of type E; or of type D; or oftype F; at P6 and P7 also D-isomers being possible; if n is 13, theamino acid residues in position 1-13 are: P1: of type C or of type D; orof type E; P2: of type E; or of type D; P3: of type C or of type D; P4:of type E or of type C; P5: of type E or of type D; P6: of type E or oftype F or the residue is Pro; P7: of type E, or the residue is Pro; P8:of type D, or the residue is Pro; P9: of type D; P10: of type E or oftype C; P11: of type C or of type D; P12: of type E; or of type D andP13: of type C or of type D; or of type E; at P6, P7 and P8 alsoD-isomers being possible; if n is 14, the amino acid residues inposition 1-14 are: P1: of type C or of type D; or of type; P2: of typeE; or of type D; P3: of type C or of type D; P4: of type D; P5: of typeE; P6: of type E; P7: of type E or of type F or of formula -A1-A69-CO—;P8: of type E or of formula —B—CO—; P9: of type D; P10: of type C; P11:of type E or of type D; P12: of type D or of type C; P13: of type E; orof type D and P14: of type C or of type D; or of type E; at P7 and P8also D-isomers being possible; if n is 15, the amino acid residues inposition 1-15 are: P1: of type C and of type D; or of type E; P2: oftype E; or of type D; P3: of type C and of type D; P4: of type E or oftype C; P5: of type C; P6: of type E or of type D; P7: of type C, or theresidue is Pro; P8: of type E or of type F, or the residue is Pro; P9:of type E or of type F, or the residue is Pro; P10: of type E; P11: oftype C; P12: of type E or of type C; P13: of type D or of type C; P14:of type E; or of type D and P15: of type C and of type D; or of type E;at P7, P8 and P9 also D-isomers being possible; and if n is 16, theamino acid residues in position 1-16 are: P1: of type D; or of type E;P2: of type E; or of type D; P3: of type C or of type D; P4: of type Eor of type D; P5: of type D; P6: of type E; P7: of type E or of type F;P8: of type E or of type F or of formula -A1-A69-CO—; P9: of type E orof formula —B-13 CO—, P10: of type D; P11: of type E; P12: of type D;P13: of type E or of type C; P14: of type C or of type D; P15: of typeE; or of type D and P16: of type C or of type D; or of type E; at P8 andP9 also D-isomers being possible.
 18. Compounds according to claim 17wherein n is 12 and the amino acid residues in position 1-12 are: P1:Leu; Arg; Lys; Tyr, Trp; Val; Gln; or 4-AmPhe; P2: Arg, Trp; or Gln; P3:Leu,; Val; Ile; or Phe; P4: Lys; Arg; Gln; or Orn; P5: Lys; or Arg; P6:Arg, Y(Bzl); or ^(D)Y(Bzl) P7: Arg, P8: Trp; Bip; 1-Nal; Y(Bzl); or Val;P9: Lys; Arg; orn; Tyr; Trp; or Gln; P10: Tyr; T(Bzl); or Y(Bzl); P11:Arg; or Tyr; and P12: Val; Arg; 1-Nal; or 4-AmPhe.
 19. A compound offormula Ia according to claim 1 wherein the template is ^(D)Pro-^(L)Pro;n is 12; and the amino acid residues in position 1-12 are: P1: Leu; P2:Arg; P3: Leu; P4: Lys; P5: Lys; P6: Arg; P7: Arg; P8: Trp; P9: Lys; P10:Tyr; P11: Arg; and P12: Val.
 20. A compound of formula Ia according toclaim 1 wherein the template is ^(D)Pro-^(L)Pro; n is 12; and the aminoacid residues in position 1-12 are: P1: Leu; P2: Arg; P3: Leu; P4: Lys;P5: Lys; P6: Arg; P7: Arg; P8: Y(Bzl); P9: Lys; P10: Tyr; P11: Arg; andP12: Val.
 21. A compound of formula Ia according to claim 1 wherein thetemplate is ^(D)Pro-^(L)Pro; n is 12; and the amino acid residues inposition 1-12 are: P1: Leu; P2: Arg, P3: Leu; P4: Lys; P5: Lys; P6: Arg;P7: Arg, P8: Trp; P9: Lys; P10: Tyr, P11: Arg; and P12:1-Nal.
 22. Acompound of formula Ia according to claim 1 wherein the template is^(D)Pro-^(L)Pro; n is 12; and the amino acid residues in position 1-12are: P1: Leu; P2: Arg, P3: Leu; P4: Lys; P5: Lys; P6: Arg, P7: Arg, P8:Bip; P9: Lys; P10: Tyr, P11: Arg; and P12: Val.
 23. A compound offormula Ia according to claim 1 wherein the template is ^(D)Pro-^(L)Pro;n is 12; and the amino acid residues in position 1-12 are: P1: Leu; P2:Arg; P3: Leu; P4: Lys; P5: Lys; P6: Arg; P7: Arg; P8: Trp; P9: Lys; P10:T(Bzl); P11: Arg; and P12: Val.
 24. A compound of formula Ia accordingto claim 1 wherein the template is ^(D)Pro-^(L)Pro; n is 12; and theamino acid residues in position 1-12 are: P1: Leu; P2: Arg; P3: Leu; P4:Lys; P5: Lys; P6: Arg; P7: Arg; P8: Trp; P9: Arg, P10: Tyr; P11: Arg;and P12: Val.
 25. A compound of formula Ia according to claim 1 whereinthe template is ^(D)Pro-^(L)Pro; n is 12; and the amino acid residues inposition 1-12 are: P1: Leu; P2: Trp; P3: Leu; P4: Lys; P5: Lys; P6: Arg;P7: Arg; P8: Bip; P9: Lys; P10: Tyr; P11: Arg; and P12: Val.
 26. Acompound of formula Ia according to claim 1 wherein the template is^(D)Pro-Phe; n is 12; and the amino acid residues in position 1-12 are:P1: Leu; P2: Arg; P3: Leu; P4: Lys; P5: Lys; P6: Arg; P7: Arg; P8: Trp;P9: Lys; P10: Tyr; P11: Arg; and P12: Val.
 27. A compound of formula Iaaccording to claim 1 wherein the template is^(D)Pro-(2R,4S)-4-[n-hexylcarbonylamino]-^(L)Pro; n is 12; and the aminoacid residues in position 1-12 are: P1: Leu; P2: Arg; P3: Leu; P4: Lys;P5: Lys; P6: Arg; P7: Arg; P8: Trp; P9: Lys; P10: Tyr, P11: Arg; andP12: Val.
 28. A compound of formula Ia according to claim 1 wherein thetemplate is ^(D)Pro-(2R,4S)-4-[cyclohexylcarbonylamino]-^(L)Pro; n is12; and the amino acid residues in position 1-12 are: P1: Leu; P2: Arg;P3: Leu; P4: Lys; P5: Lys; P6: Arg; P7: Arg, P8: Trp; P9: Lys; P10: Tyr;P11: Arg; and P12: Val.
 29. A compound according to claim 1 wherein thetemplate is of formula (c1) wherein R²⁰ is H; R³⁵ is methyl; R³⁶ ismethoxy; R³⁷ is H and R³⁸ is H; n is 12; and the amino acid residues inposition 1-12 are: P1: Leu; P2: Arg; P3: Leu; P4: Lys; P5: Lys; P6: Arg;P7: Arg; P8: Trp; P9: Lys; P10: Tyr, P11: Arg; and P12: Val.
 30. Acompound of formula Ia according to claim 1 wherein the template is^(D)Pro-^(L)Pro; n is 12; and the amino acid residues in position 1-12are: P1: Arg; P2: Trp; P3: Leu; P4: Lys; P5: Lys; P6: Arg; P7: Arg; P8:Trp; P9: Lys; P10: Tyr; P11: Tyr, and P12: Val.
 31. A compound offormula Ia according to claim 1 wherein the template is ^(D)Pro-^(L)Pro;n is 12; and the amino acid residues in position 1-12 are: P1: Leu; P2:Trp; P3: Leu; P4: Lys; P5: Lys; P6: Arg; P7: Arg; P8: Trp; P9: Lys; P10:Tyr; P11: Tyr, and P12: Arg.
 32. A compound of formula Ia according toclaim 1 wherein the template is ^(D)Pro-^(L)Pro; n is 12; and the aminoacid residues in position 1-12 are: P1: Arg; P2: Trp; P3: Leu; P4: Lys;P5: Lys; P6: Arg; P7: Arg; P8: Trp; P9: Lys; P10: Tyr; P11: Tyr; andP12: Arg.
 33. A compound of formula Ia according to claim 1 wherein thetemplate is ^(D)Pro-^(L)Pro; n is 12; and the amino acid residues inposition 1-12 are: P1: Leu; P2: Arg, P3: Leu; P4: Lys; P5: Lys; P6:^(D)Y(Bzl); P7: Arg; P8: Trp; P9: Lys; P10: Tyr, P11: Arg; and P12: Val.34. A compound of formula Ia according to claim 1 wherein the templateis ^(D)Pro-^(L)Pro; n is 12; and the amino acid residues in position1-12 are: P1: Arg; P2: Bip; P3: Leu; P4: Lys; P5: Lys; P6: Arg; P7: Arg;P8: Trp; P9: Lys; P10: Tyr, P11: Tyr; and P12: Arg.
 35. A compound offormula Ia according to claim 1 wherein the template is ^(D)Pro-^(L)Pro;n is 12; and the amino acid residues in position 1-12 are: P1: Lys; P2:Trp; P3: Leu; P4: Lys; P5: Lys; P6: Arg; P7: Arg; P8: Trp; P9: Lys; P10:Tyr, P11: Tyr, and P12: Arg.
 36. A compound of formula Ia according toclaim 1 wherein the template is ^(D)Pro-^(L)Pro; n is 12; and the aminoacid residues in position 1-12 are: P1: Tyr, P2: Trp; P3: Leu; P4: Lys;P5: Lys; P6: Arg; P7: Arg; P8: Trp; P9: Lys; P10: Tyr; P11: Tyr, andP12: Arg.
 37. A compound of formula Ia according to claim 1 wherein thetemplate is _(D)Pro-^(L)Pro; n is 12; and the amino acid residues inposition 1-12 are: P1: Trp; P2: Trp; P3: Leu; P4: Lys; P5: Lys; P6: Arg;P7: Arg; P8: Trp; P9: Lys; P10: Tyr; P11: Tyr; and P12: Arg.
 38. Acompound of formula Ia according to claim 1 wherein the template is^(D)Pro ^(L)Pro; n is 12; and the amino acid residues in position 1-12are: P1: Val; P2: Trp; P3: Leu; P4: Lys; P5: Lys; P6: Arg; P7: Arg; P8:Trp; P9: Lys; P10: Tyr; P11: Tyr; and P12: Arg.
 39. A compound offormula Ia according to claim 1 wherein the template is ^(D)Pro-^(L)Pro;n is 12; and the amino acid residues in position 1-12 are: P1: Gln; P2:Trp; P3: Leu; P4: Lys; P5: Lys; P6: Arg, P7: Arg; P8: Trp; P9: Lys; P10:Tyr; P11: Tyr; and P12: Arg.
 40. A compound of formula Ia according toclaim 1 wherein the template is ^(L)Pro-^(L)Pro; n is 12; and the aminoacid residues in position 1-12 are: P1: -Leu; P2: Arg; P3: Leu; P4: Lys;P5: Lys; P6: Y(Bzl); P7: Arg; P8: Trp; P9: Lys; P10: Tyr; P11: Arg; andP12: Val.
 41. Enantiomers of the compounds of formulae Ia and Ib asdefined in claim
 1. 42. Compounds according to any one of claims 1 to 41for use as therapeutically active substances.
 43. A pharmaceuticalcomposition containing a compound according to any one of claims 1 to 41and a pharmaceutically inert carrier.
 44. Compositions according toclaim 43 in a form suitable for oral, topical, transdermal, injection,buccal, transmucosal, pulmonary or inhalation administration. 45.Compositions according to claim 43 or 44 in form of tablets, dragees,capsules, solutions, liquids, gels, plasters, creams, ointments, syrups,slurries, suspensions, sprays, nebulisers or suppositories.
 46. The useof compounds according to any one of claims 1 to 41 for the manufactureof a medicament for treating or preventing infections or diseasesrelated to such infections, said infections being in particular cysticfibrosis lung infections, or for the manufacture of a medicament usefulagainst malignant cells for treatment of cancer.
 47. The use ofcompounds according to any one of claims 1 to 41 as disinfectants orpreservatives for foodstuffs, cosmetics, medicaments and othernutrient-containing materials.
 48. The use of compounds according toclaims 141 for preventing surfaces from microbial colonisation.
 49. Aprocess for the manufacture of compounds according to any one of claims1 to 40 which process comprises (a) coupling an appropriatelyfunctionalized solid support with an appropriately N-protectedderivative of that amino acid which in the desired end-product is inposition a/2, n/2+1 or n/2−1 if n is an even number and, respectively,in position n/2+½ or n/2−½ if n is an odd number, any functional groupwhich may be present in said N-protected amino acid derivative beinglikewise appropriately protected; (b) removing the N-protecting groupfrom the product thus obtained; (c) coupling the product thus obtainedwith an appropriately N-protected derivative of that amino acid which inthe desired end-product is one position nearer the N-terminal amino acidresidue, any functional group which may be present in said N-protectedamino acid derivative being likewise appropriately protected; (d)removing the N-protecting group from the product thus obtained; (e)repeating, if necessary, steps (c) and (d) until the N-terminal aminoacid residue has been introduced; (f) coupling the product thus obtainedto a compound of the general formula

 wherein

 is as defined above and X is an N-protecting group or, if

 is to be group (a1) or (a2), above, alternatively (fa) coupling theproduct obtained in step (d) or (e}.with an appropriately N-protectedderivative of an amino acid of the general formula HOOC—B—H  III orHOOC-A-H  IV  wherein B and A are as defined above, any functional groupwhich may be present in said N-protected amino acid derivative beinglikewise appropriately protected; (fb) removing the N-protecting groupfrom the product thus obtained; and (fc) coupling the product thusobtained with an appropriately N-protected derivative of an amino acidof the above general formula IV and, respectively, III, any functionalgroup which may be present in said N-protected amino acid derivativebeing likewise appropriately protected; (g) removing the N-protectinggroup from the product obtained in step (f) or (fc); (h) coupling theproduct thus obtained to an appropriately N-protected derivative of thatamino acid which in the desired end-product is in position n, anyfunctional group which may be present in said N-protected amino acidderivative being likewise appropriately protected; (i) removing theN-protecting group from the product thus obtained; (j) coupling theproduct thus obtained to an appropriately N-protected derivative of thatamino acid which in the desired end-product is one position further awayfrom position n, any functional group which may be present in saidN-protected amino acid derivative being likewise appropriatelyprotected; (k) removing the N-protecting group from the product thusobtained; (l) repeating, if necessary, steps (j) and (k) until all aminoacid residues have been introduced; (m) if desired, selectivelydeprotecting one or several protected functional group(s) present in themolecule and appropriately substituting the reactive group(s) thusliberated, (o) detaching the product thus obtained from the solidsupport; (p) cyclizing the product cleaved from the solid support, (q)if, desired (qa) forming one or several interstrand linkage(s) betweenside-chains of appropriate amino acid residues at opposite positions ofthe β-strand region; and/or (qb) connecting two building blocks of thetype of formula Ia via a bridge -G1-L-G2-; (r) removing any protectinggroups present on functional groups of any members of the chain of aminoacid residues and, if desired, any protecting group(s) which may inaddition be present in the molecule; and (s) if desired, converting theproduct thus obtained into a pharmaceutically acceptable salt orconverting a pharmaceutically acceptable, or unacceptable, salt thusobtained into the corresponding free compound of formula I or into adifferent, pharmaceutically acceptable, salt.
 50. A modification of theprocess of claim 49 for the manufacture of compounds according to claim41 in which enantiomers of all chiral starting materials are used.